Ullmanns Encyclopedia of Industrial Chemistry

Antipsychotics/Neuroleptics
Marie-Christine DuBROEUca Rhone-Poulenc Rorer, Vitry-Siir-Scine, Trance

Jean-Marie Stutzmann, Rhone-Poulenc Rorer, Vitry-Sur-Seine, Trance
Franco Manfre, Rhone-Poulenc Rorer, Vitry-Sur-Seine, Trance
Marc Capet, Rhone-Poulenc Rorer, Vitry-Sur-Seine, France
Georg Andrees Bohme, Rhone-Poulenc Rorer, Vitry-Sur-Seine, T’rance
1. Introduction............................. 588 3.3. Monoamine Oxidase

Inhibitors (MAOI)................. 622
2. Neuroleptics............................. 588
3.3.1. Hydrazine Derivatives............... 622
2.1. Phenothiazines....................... 589 3.3.2. Nonhydrazine Derivatives.... 624
2.1.1. 10-Aminoalkyl-Substituted 3.3.3. Reversible MAO-A Inhibitors . . 625
Phenothiazines........................... 590
3.4. Inhibitors of Serotonin Uptake 627
2.1.2. 10-Piperidylalkyl-Substituted
Phenothiazines........................... 591 3.5. Lithium..................................... 630
2.1.2.1. Piperidylethyl-Substituted 3.6. Miscellaneous Antidepressants 631
Phenothiazines........................... 592
3.7. Antidepressants Under
2.1.2.2. Piperidinopropyl-Substituted
Development.......................... 633
Phenothiazines........................... 592
2.1.3. 1-Piper azinylpropyl-Substituted 4. Anxiolytics................................ 634
Phenothiazines........................... 593 4.1. Benzodiazepines.................... 635
2.2. Thioxanthenes....................... 596 4.1.1. 1,4-Benzodiazepines.................. 636
4.1.2. Other Benzodiazepines............ 643
2.3. Piperidinobutyrophenones. . 597
4.2. Carbamates............................. 644
2.4. Diphenylbutylpiperidines. . . 600
4.3. Other Anxiolytics................. 646
2.5. Dibenzazepines and Analogues 602
4.4. Anxiolytics Under
2.5.1. Dibenzazepines........................... 603
Development.......................... 648
2.5.2. Piperazinyl Derivatives............ 604
5. Geriatric Drugs....................... 649
2.6. Benzamides.............................. 605
5.1. Nootropics................................ 650
2.7. Miscellaneous Neuroleptics . 608
5.2. Cholinergic Drugs................. 651
2.8. Neuroleptics Under
5.2.1. Choline Analogues..................... 652
Development.......................... 609
5.2.2. Cholinesterase Inhibitors .... 653
3. Antidepressants....................... 610 5.2.3. Thyroliberin Analogues............ 654
3.1. Tricyclic Antidepressants... 610 5.3. Metabolically Active Drugs. . 654

3.1.1. Inhibitors of Noradrenaline and/
5.4. Antidepressants....................... 657
or Serotonin Uptake.................. 611
3.1.2. Enhancers of Uptake.................. 617 5.5. Miscellaneous Geriatric Drugs 658
3.1.3. Inhibitors of Dopamine Uptake 617 5.6. Geriatric Drugs Under

3.1.4. Other Tricyclic Antidepressants. 617 Development.......................... 659
3.2. Tetracyclic Antidepressants . 620 6. References................................ 660
587
A n tip sy c h o tic s/N e u ro le p tic s
I Introduction
The term “psychopharmacological agents” refers to the wide variety of substances
that affect the mind. These include not only agents that are used in clinical practice to
alleviate or correct symptoms of psychiatric illnesses, but also drugs of abuse that are
self-administered by humans for their subjective effects on the mood. The latter
generally originate from natural preparations and have been known for a long time
(e.g., caffeine, opiates, nicotine, cocaine). The present article focuses on psychoactive
drugs that are of therapeutic significance in psychiatry. Neurological medications such
as hypnotics (-^ Sedatives), analgesics (->• Analgesics and Antipyretics), and sedatives
are treated in other chapters of this book, see also —>• Neuropharmaceutical Agents.
The beginning of the modern era of psychopharmacology began in the early 1950s
with the discovery of the antipsychotic properties of chlorpromazine. Since then, the
therapeutic armament has successively benefited from the discovery of antidepressive
drugs, anxiolytics or minor tranquilizers, and cognition enhancers that are believed to
compensate for age-associated memory impairments and dementias. The psychophar
macological agents will be reviewed following this chronology.
Several classifications based on chemical structures, pharmacological properties, or
clinical efficacy have been proposed for psychopharmacological agents, but none
appears entirely satisfactory. Currently available drugs work symptomatologically,
but do not alleviate the causes of the illnesses. The classification used here is based
on the medical use of the psychopharmacological agents. The individual compounds
are divided into categories with a common structural feature or a similar mode of
action; they have been selected on the basis of their historical importance and their
present world market. Several substances undergoing clinical development have also
been reviewed. Lists of trade names are not exhaustive.
Some background of neurobiology has been included when necessary for the under
standing of the mechanism of action of the drugs. Since the early 1970s knowledge of
the central nervous system has become increasingly complicated by the discovery of
brain processes with which psychoactive drugs may interact. A comprehensive account
of the present state of the art in this field can be found elsewhere Neuropharma
ceutical Agents).
2. Neuroleptics
Psychiatric disorders are generally divided into two classes. Psychoses (e.g., schizo
phrenia, mania, and depression) are severe diseases believed to result from the dysfunc
tion of some brain processes. Neuroses refer to less debilitating affections related to
exagerated reactions to life events otherwise considered as normal (e.g., anxiety).
The neuroleptics, also called major tranquilizers or antipsychotics, act on schizophrenia,
the most prominent form of psychosis (1% of the population is affected). Until the
588
N e u ro le p tic s
twentieth century, no treatment was available for those suffering from psychiatric
disorders, particularly schizophrenia. Early medications are of little significance today
(e.g., extracts of ergot or Rauwolfia serpentina). The observation of the antipsychotic
properties of chlorpromazine and its introduction in clinical practice by Delay and
Deniker in 1952 constituted a major breakthrough in the treatment of psychotic
conditions [1]. This molecule, initially tested for its sedative properties, gave rise to
the phenothiazine family. Several other families of neuroleptics were discovered soon
after, including the thioxanthenes, butyrophenones, dibenzazepines, their piperazinyl
derivatives and benzamides. The symptoms of schizophrenia include positive signs,
such as psychomotor agitation, delusions, hallucinations, and negative symptoms
including loss of social interaction and affective flattening. The observation that
clinically effective neuroleptics have dopamine antagonist properties has led to the
widely accepted hypothesis that an overactivity of this neurotransmitter system is
involved in the disease 121-[5j. Neuroleptics have a high affinity for Di and D2
dopamine receptors, the D2 receptors being of particular importance for their clinical
effectiveness. The recent discovery of additonal dopamine receptor subtypes may
underlay the activity of several atypic neuroleptics 16]. Moreover, interaction with
serotoninergic processes in the brain may be involved in the action of certain anti-
psychotics. The experimental pharmacology of classical neuroleptics is characterized by
their capacity to induce catalepsy and to antagonize the behavioral effects of dopami-
nomimetic agents (e.g., apomorphine). They also decrease body temperature, potenti
ate the activity of hypnotic and analgesic drugs, and impair conditioned avoidance
responses. The dopamine antagonist properties are also related to the neurological side
effects of these compounds (akathisia, dystonia, tardive dyskinesia). Other side effects
arise from interference with dopaminergic systems in the hypothalamus or pituitary
(e.g., increased prolactin levels). Neuroleptics can also be used against nausea and
vomiting, and some are useful in the treatment of neuropsychiatric syndromes (e.g.,
Huntington's disease).
2.1. Phenothiazines
Phenothiazine itself was first synthesized by the end of the ninteenth century and
used as a dye.
9 I
H
1
10
Its insecticidal and anthelmintic properties were described in the mid 1930s. The
observation of the strong sedative properties of promethazine, a close analog with
antihistaminic activity, prompted the synthesis of other centrally acting phenothiazines.
589
This project resulted in the discovery of chlorpromazine, the prototype antipsychotic
drug [1].
The nitrogen atom of phenothiazine is substituted by aminoalkyl, piperidyl, or
piperazinylalkyl side chains. The length of the side chain is critical: neuroleptic
derivatives have three carbon atoms between the heterocyclic nitrogen and the tertiary
nitrogen of the side chain. Compounds with only two carbon atoms show strong
antihistaminic or anticholinergic activities.
The neuroleptic phenothiazines are usually synthesized by condensing a 2-substi-
tuted phenothiazine with halogenoalkylamines in the presence of a base:
X
I R'
2.1.1. I O-Aminoalkyl-Substituted
Phenothiazines
The aliphatic side-chain derivatives are sedatives and act on cholinergic, histami-
nergic, dopaminergic, and adrenergic receptors [71.
R
I
R = (CH2)3N(CH3)2: promazine (X=H); chlorpro
mazine (X = C1); trinupromazine (X = CF3); acepro-
mazine (X = COCH3)
R = (CH2)CH(CH3)CH2N(CH3)2: alimemazine (X = H);

levomepromazine (X = OCH3); cyamemazine (X =CN)
Promazine [58-40-2], 10-(3-dimethylaminopropyl)-10//-phenothiazine, C17H20N2S,

Mr 284.41, bp (0.04 kPa) 203 - 210 °C, for preparation see [8].
Trade Names: Atarzine (Saunders, Canada), Calmotal (SIT, Italy), Centractyl (Astra), Eliranol (Wyeth),
Neuroplegil (Gentili, Italy), Prazine (Wyeth), Prozine (Hauck, USA), Sediston (Serono), Talofen
(Pierrel, Italy), Tranquazine (Anthony, USA).
Chlorpromazine [50-53-3], 2- chloro-10-(3-dimethylaminopropyl)-10//-phenothia-

zine, C17H19CIN2S, Mr 318.88, bp (0.106 kPa) 200-205 °C, for preparation see [9].
Trade Names: Elmarine (Marion, USA), Esmind (Otsuka, Japan), Largactil (Rhone-Poulenc), Megaphen
(Bayer), Promactil (Wassermann, Spain), Promapar (Parke Davis), Promexin (Meiji, Japan), Propa-
590
N e u ro le p tic s
phenin (Deutsches Hydrierwerk, Germany), Prozin (Lusofarmaco, Italy), Psychozine (Forest, USA),
Thorazine (SKF).
Triflupromazine [146-54-3], 10-(3-dimethylaminopropyl)-2-trifluoromethyl-10H-

phenothiazine, C18H19F3N2S, Mr 352.49, bp (0.053 kPa) 162 -164 °C, for preparation
see [10].
Trade Names: Psyquil (Squibb, France), Siquil (Squibb, Belgium), Vesprin (Squibb, Canada).
Acepromazine [61-00-7], 2-acetyI-10-(3-dimethylaminpropyl)-10//-phenothiazine,

C19H22N2OS, Mr 326.47, bp (0.066 kPa) 220-240 °C, for preparation see [11].
Trade Names: ACP C-VET (Arovet, Switzerland), Calmivet (Vetoquinol, France), Neurotranq (Alfasan,
The Netherlands), Sedalin (Chassot, Switzerland).
Alimemazine [84-96-8], 10-(3-dimethylamino-2-methylpropyl)-10H-phenothiazine,

C18H22N2S, Mr 298.44, mp 68 °C, for preparation see [12].
Trade Names: Panectyl (Specia, France), Spansule (Herbert, USA), Temaril (SKF), Theralene (Rhone-
Poulenc), Vallergan (May & Baker).
Levomepromazine [60-99-1], 2-methoxy-10-(3-dimethylamino-2-methylpropyl)-

10i/-phenothiazine, C19H24N2OS, Mr 328.46, mp 190 °C, for preparation see [12].
Trade Names: Levomezine (Toho, Japan), Levomeprome (Lederle), Levonormal (Sawai, Japan), Min-
ozinan (Specia), Neurocil (Bayer), Nozinan (Specia), Procrazine (Toyo Pharmar, Japan), Softnin
(Dainippon, Japan), Veractil (Rhone-Poulenc), Sinogan (Rhone, Spain).
Cyamemazine [3546-03-0], 2- cyano-10-(3-dimethylamino-2-methylpropyl)-10/f-

phenothiazine, C19H21N3S, Mr 323.47, mp 89-96T, for preparation see [13].
Trade Name: Tercian (TheraplLx, France).
2.1.2. 10-Piperidylalkyl-Substituted
Phenothiazines
The phenothiazines containing piperidyl side chains have a relatively high neuro
leptic potency; some induce less extrapyramidal side effects than chlorpromazine. They
show anticholinergic and adrenolytic activity.
591
2.1.2.1. Piperidylethyl-Substituted Phenothiazines
Thioridazine X = SCHj
Mesoridazine X = SOCH3
Sulforidazine X = SOjCHj
Thioridazine [50-52-2], 2-methylmercapto-10-[2-(l-methyl-2-piperidyl)ethyl]-10//-

phenothiazine, C21H26N2S2, Mr 370.56, mp 72-74T, for preparation see [14].
Trade Names: Mallorol, Meleril, Mellaril, Melleril (Sandoz), Novoridazine (Novopharm, Canada),
Orsanil (Orion, Finland), Ridazin (Taro, Israel), Stalleril (Pharmacal, Finland), Thioril (ICN, Canada).
Mesoridazine [5588-33-0], 2-methylmercapto-10-[2-(l-methyl-2-piperidyl)ethyl]-

10//-phenothiazine-2-oxide, C21H26N2OS2, Mr 386.59, mp 115-120 °C, for preparation
see [15].
Trade Names: Calodal (Heyden, Germany), Lidanil (Sandoz), Serentil (Sandoz).
Sulforidazine [14759-06-9], 2-methylsulfonyl-10-[2-(l-methyl-2-piperidyl)ethyl]-10//-

phenothiazine, C21H26N2O2S2, Mr 402.57, mp 121-123 °C, for preparation see [16].
Trade Name: Inofal (Sandoz, Germany).
2.1.2.2. Piperidinopropyl-Substituted Phenothiazines
Pipamazine
Pericyazine
Piperacetazine
(CH,),OH
Pipotiazine
Spiclomazine
Pipamazine [84-04-8], 10-[3-(4- carbamoylpiperidino)propy]]-2-ch]oro-10//-phe-

nothiazine, Q1H24CIN3OS, Mr 401.97, mp 139 °C, for preparation see [17]. Pipamazine
is also used as an antiemetic.
592
N e u ro le p tic s
Trade Names: Nometine (Searle), Nansidol, Mornitine.
Pericyazine [2622-26-6], 2- cyano-10-[3-(4-hydroxypiperidino)propyl]-10//-phe-

nothiazine, C21H23N3OS, M, 365.50, mp 116-117 °C, for preparation see [18].
Trade Names: Amplan (Taisho, Japan), Aolept (Bayer), Apamin (Yoshitomi, Japan), Nemactil (Specia),
Neulactil (May & Baker), Neuleptil (Rhone-Poulenc).
Piperacetazine [3819-00-9], 2-acetyl-10-[3-[4-(2-hydroxyethyl)piperidino]propyl]-

10//-phenothiazine, C24H30N2O2S, Mr 410.59, mp 100-110 °C, for preparation see [19].
Trade Name: Quide (Merrell Dow).
Pipotiazine [39860-99-6], 10-{3-[4-(2-hydroxyethyl)piperidino]propyI}-AJ,Ar-dimethyl-

10//-phenothiazine-2-sulfonamide, C24H33N3O3S2, Mr 475.66, mp 58-59°C, for pre
paration see [20].
Trade Names: Piportil (Rhodia, Brazil), Piportil Depot (May & Baker), Piportil Longum (Specia),
Piportyl (Rhone-Poulenc).
Spiclomazine [24527-27-3], 8-[3-(2- chloro-10//-phenothiazin-10-yl)propyl]-l-thia-

4,8-diazaspirol[4,5]decan-3-one, C22H24CIN3OS2, Mr 446.02, mp 154-156 °C, for pre
paration see [21].
Trade Name: Diceplon (Yoshitomi, Japan).
2.1.3. I -Piperazinylpropyl-Substituted
Phenothiazines
The piperazine derivatives are the most potent phenothiazine neuroleptics. They
have only mild sedative effects, induce strong extrapyramidal side effects, and have a
lower propensity for inducing autonomic side effects due to the lack of high-affinity
binding to cholinergic and adrenergic receptors.
Perazine [84-97-9], 10-[3-(4-methyl-l-piperazinyl)propyl]-10//-phenothiazine,

C20H25N3S, Mr 339.49, mp 51-53T, for preparation see [22].
Trade Name: Taxilan (Promonta).
593
V
Z
Perazine X=H
Prochlorperazine X = C1
o Trifluoperazine X = CF3
JC
R = CHj
Thioproperazine X = S03N(CH3)3
uX Butaperazine X = COICHjIjCHj j
Perphenazine X = C1 S
Fluphenazine X = CF3 1
c R = CH^CHjOH
< Acetophenazine X = COCH3 [
Carphenazine X = COCH3CH3 J
Prochlorperazine [58-38-8], 2- chloro-10-[3-(4-methyl-l-piperazinyl)propyl]-10//-

phenothiazine, C20H24CIN3S, Mr 373.94, mp 228 °C (dimaleate), for preparation see
[23].
Trade Names: Anti-Naus (Protea, Australia), Bucastem (Reckitt & Colman, UK), Compazine (SKF),
Nipodal (Bayer), Normalmin (Sawai, Japan), Stemetil (Farmitalia, Italy), Tementil (Specia), Vertigon
(SKF).
Trifluoperazi ne [117-89-5], 2-trifluoromethyI-lO- [ 3-(4-methyl-l-piperazinyI)propyI]-

10//-phenothiazine, C21H24F3N3S, Mr 407.49, bp (0.08 kPa) 202-210 °C, for prepara
tion see [24].
Trade Names: Eskazine (SKF), Jatroneural (Rohm Pharma, Germany), Modalina (Maggioni-Winthrop,
Italy), Novolurazine (Novapharm, Canada), Pentazine (Pentagone, Canada), Solazine (Horner, Ca
nada), Stelazine (SKF), Telazin (SKF), Terfluzine (Theraplix, France), Trifluoper-Ez-Ets (Barlowe Cote,
Canada).
Thioproperazine [316-81-4], 10-[3-(4-methyl-l-piperazinyl)propyl]-Ar,A(-dimethyl-

10//-phenothiazine-2-sulfonamide, C22H30N4O2S2, Mr 446.64, mp 140 °C, for prepara
tion see [25].
Trade Names: Majeptil (Specia, France), Mayeptil (Rhodia, Argentina).
Butaperazine [653-03-2], 2-butyryl-10-[3-(4-methyl-l-piperazinyl)propyl]-10//-phe-

nothiazine, C24H31N3OS, Mr 409.60, bp (0.006 kPa) 270-280 °C, for preparation see
[26].
Trade Names: Randolectil (Bayer, Argentina), Repoise (Robins, USA).
Perphenazine [58-39-9], 2-chloro-10-{3-[4-(2-hydroxyethyl)-l-piperazinyl]propyl}-

10//-phenothiazine, C21H21CIN3OS, Mr 403.97, mp 94-100 °C, for preparation see [27].
594
N e u ro le p tic s
Trade Names: Decetan (Merck), Etaperazin (Medexport, lEC), Fentazin (Allen & Hanburys, UK), F-
Mon (Kuroishi, Japan), Phenazine (ICN, Canada), Trilafon (Schering), Trilifan (Cetrane, France).
Metofenazate [388-51-2], C31H36CIN3O5S, Mj- 598.18, rnp 102 — 107 C, is the 3,4,5-
trimethoxybenzoate of perphenazine; for preparation see [28].
Trade Name: Frenolon (Egis, Hungary).
Thiopropazate [84-06-0], C23H28CIN3O2S, 446.00, bp (0.1 kPa) 214 — 218 C, is

the acetate of perphenazine; for preparation see [29].
Trade Names: Dartal, Dartalan (Searle).
Fluphenazine [69-23-8], 10-{3-[4-(2-hydroxyethyl)-l-piperazinyl]propyl}-2-trifluoro-

methyl-10//-phenothiazine, C22H26F3N3OS, Mr 437.52, bp (0.066 kPa) 268-274 °C,
for preparation see [30].
Trade Names: Anatensol, Calmansial, Dapotum, Moditen, Prolbdn (Squibb); Eutimox (Soc. Gen. de
Pharmacia, Switzerland); Lyorodin (Deutsches Hydrierwerk, Germany); Omca (Heyden, Germany);
Pacinol, Permitil, Trancin (Schering); Siqualine (Iquinosa, Spain).
Acetophenazine [2751-68-0], 2-acetyl-10-{3-[4-(2-hydroxyethyl)-l-piperazinyl]pro-

pylHO/f-phenothiazine, C23H29N3O2S, M, 411.57, mp 167-168 T, for preparation
see [31].
Trade Name: Tindal (Schering, UK).
Carphenazine [2622-30-22], 10-[3-[4-(2-hydroxyethyl)-l-piperazinyl]propyl]-2-pro-

pionyl-10//-phenothiazine, C24H31N3O2S, Mr 425.6, mp 175-177 °C, for preparation
see [32]
Trade Name: Proketazine (Wyeth, USA).
Two other compounds are analogous to the phenothiazines described above:
Homofenazine [ 3833-99-6 ], 10-{3-[hexahydro-4-(2-hydroxyethyl)-l,4-diazepine-l-yl]-

propyl}-2-trifluoromethyl-10H-phenothiazine, C23H28F3N3OS, Mr 451.52, bp (0.133 kPa)
230-240°C, is homologous to fluphenazine; for preparation see [33].
Trade Name: Pasaden (Homburg).
595
Prothipendyl [1225-65-6], 10-(3-dimethylaminopropyl)-10//-pyrido[3,2-Z>] [l,4]ben-

zothiazine, C16H19N3S, M,. 285.42, bp (0.093 kPa) 217-219 °C, for preparation see
[34], is analogous to promazine (azaphenothiazine) with general properties similar
to those of chlorpromazine.
CHjCHjCH3N(CH3)j
Trade Names: Dominal (Astra, Germany), Tolnate (SKF, UK).
2.2. Thioxanthenes
The thioxanthene neuroleptics are chemically and pharmacologically related to the
phenothiazines. Activity resides with the cis isomers. The aminoalkyl and piperaziny-
lalkyl side chains are similar to those of the phenothiazines, producing comparable
potencies and side effects. The thioxanthenes are prepared by condensing the tricyclic
ketone with the Grignard reagent of the desired aminoalkyl chain. The resulting alcohol
is then dehydrated in an acidic medium.
HCl
X
.R
Chlorprothixene [113-59-7], 2- chloro-9-(3-dimethylaminopropylidene)-9//-thioxan-

thene, CisHigClNS, 315.86, mp 97-98T, for preparation see [351.
Trade Names: Cloxan (Orion, Finland); Paxyl (Ikepharm); Tactaran (Roche), Taractan, Tarasan,
Taratan (Roche); Truxal, Truxaletten (Lundbeck).
Thiothixene [3313-26-6], cA-9-[3-(4-methyl-piperazinyl)propylidene]-Ar,Ar-dimethyl-

9//-thioxanthene-2-sulfonamide C23H29N3O2S2, Mr 443.63, mp 147-149 °C, for pre
paration see [36].
596
3
V
z
Trade Names: Navane, Navaron, Orbinamon (Pfizer).
Flupentixol [2709-56-0], 9-{3-[4-(2-hydroxyethyl)-l-piperazinyl]propylidene}-2-tri-

fluoromethyl-9H-thioxanthene, C23H25F3N2OS, M, 434.54, mp 236-240 °C, is prepared
with the alcoholic function protected as a benzyl ether. This protection is removed by
catalytic hydrogenation at the end of the synthesis 1371.
k^N-CH^CHÔH
Trade Names: Depixol, Fluanxol (Lundbeck, Denmark), Emergil (Labaz), Metamin (Takeda, Japan),
Phrenixol (Ikepharm, Israel), Siplarol (Farmitalia, Italy).
Clopenthixol [982-24-1], 2- chloro-9-{3-l4-(2-hydroxyethyl)-l-piperazinyllpropyli-

dene}-9//-thioxanthene, C22H25CIN2OS, Mj- 400.99, mp 250-260 °C (dihydrochloride),
for preparation see 1381.
Trade Names: Ciatyl, Sordena, Sordinol (Kefalas).
Zuclopenthixol [53772-83-1], C22H25CIN2OS, M, 400.99, mp 84-85T, is the cis

isomer of clopenthixol 1381.
Trade Names: Cisodinol, Clopixol (Lundbeck, Denmark); Sedanxol (Tropon, Germany).
2.3. Piperidinobutyrophenones
The piperidinobutyrophenones are the most potent neuroleptics (benperidol, triflu
peridol). They have a higher binding selectivity for D2 than for Di receptors, lack
affinity for cholinergic receptors, and show less sedative side effects 17]. The buty-
rophenones are prepared by condensing the relevant piperidine derivative with
4- chloro-l-(4-fluorophenyl)-l-butanone.
597
o
F
Cl
4-Chloro-l -(4-fluorophenyl)-l -butanone
Haloperidol [52-86-8], 4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyro-

phenone, C21H23CIFNO2, 375.88, mp 148-149 °C, for preparation see [39]. Halo
peridol is also used in the management of Gilles de la Tourette's syndrome.
Trade Names: Brotopon (Pfizer), Duraperidol (Durachemie, Germany), Haldol (Janssen), Halojust
(Horita, Japan), Halopidol (Johnson & Johnson), Halosten (Shionogi, Japan), Keselan (Sumitomo,
Japan), Linton (Yoshitomi, Japan), Novoperidol (Novopharm, Canada), Selezyme (Sawai, Japan),
Serenace (Searle).
Bromperidol [10457-90-6], 4-[4-(4-bromophenyl)-4-hydroxypiperidinol-4'-fluorobu-

tyrophenone, C2iH23BrFN02, M, 420.33, mp 155-158 °C [39].
Trade Names: Azuren, Bromidol, Impromen (Janssen), Tesoprel (Organon, Germany).
Moperone [ 3871-82-7 ], 4 -fluoro-4-[4-hydroxy-4-(4-methy[pheny[)piperidino]butyro-

phenone, C22H26FNO2, 355.46, mp 118-119 °C, for preparation see [40].
Trade Names: Luvatren, Luvatrena, Luvatrene (Cilag-Chemie).
Fluanisone [1480-19-9], 4'-fluoro-4-[4-(2-methoxypheny[)-l-piperazinyl]butyrophe-

none, C21H25FN2O2, 356.45, mp 205 °C, for preparation see [41].
CH3O
Trade Name: Sedaland (Delalande, France).
598
Trifluperidol [749-13-3], 4'-fluoro-4-[4-hydroxy-4-(3-trifluoromethylphenyl)piperi-
N e u ro le p tic s
dino]-butyrophenone, C22H23F4NO2, M, 409.43, mp 200-201 °C, for preparation see
[42].
Trade Name: Triperidol (Lagap, UK).
Pipamperone [1893-33-0], 4-[(4-carbamoyl-4-piperidino)-4'-fluorobutyrophenone,

C21H30FN3O2, Mr 375.49, mp 124-126 T (dihydrochloride), for preparation see [43].
Trade Names: Dipiperal (Johnson & Johnson), Dipiperon (Janssen, France), Piperonil (Lusofarmaco,
Italy), Propitan (Esai, Japan).
Spiperone [749-02-0], 8-[3-(4-fluorobenzoy]propyl]-4-oxo-l-pheny]-l,3,8-triazas-

piro[4,5]-decane, C23H26FN3O2, M, 395.48, mp 190-194 T, for preparation see [44].
Trade Name: Spiropitan (Japan).
Benperidol [2062-84-2] l-{l-[3-(4-fluorobenzoyl)propy]]-4-piperidyl}-2-benzimidazo-

linone, C22H24FN3O2, M, 381.45, mp 170-172 °C, for preparation see [45].
Trade Names: Anquil (Janssen, UK), Frenactil (Janssen, Belgium), Clianimon (Tropon, Germany),
Psicoben (Ravizza, Italy).
Timiperone [57648-21-2], l-{l-[3-(4-fluorobenzoy])propyl]-4-piperidyl}-2-mercapto-

benzimidazole, C22H24FN3OS, M, 397.5, mp 201-203 T, for preparation see [46].
599
A n tip sy c h o tic s/N e u ro le p tii
F
Trade Name: Tolopelon (Daichi, Japan).
Droperidol [548-73-2], l-{l-[3-(4-fluorobenzoyl)propyl]-l,2,3,6-tetrahydro-4-pyri-

dyl}-2-benz-imidazolinone, C22H22FN3O2, M^. 379.4, mp 145 —146 °C, for preparation
see [47]. Droperidol shows a long duration of action. It is used in conjunction with an
analgesic (e.g., fentanyl) to induce neuroleptanalgesia in anesthesiology.
Trade Names: Dehydrobenperidol, Droleptan (Janssen), Inapsine (McNeil, USA), Sintodian (Farmitalia
Carlo Erba).
Melperone [3575-80-2], 4'-fluoro-4-(4-methylpiperidino)butyrophenone, C16H22FNO,

Mr 263.37, mp 209-211T (hydrochloride), for preparation see [48]. Unlike the other
butyrophenones, melperone shows only weak affinity for the dopamine receptors. It
seems to act through the serotonin 5-HT2 receptor for serotonin (5-hydroxytryptamine,
5-HT). Melperone is one of the noncataleptogenic neuroleptics with a low tendency for
inducing extrapyramidal side effects.
Trade Names: Buronil (Ferrosan, Italy), Eunerpan (Nordmark, Germany).
2.4. Diphenylbutylpiperidines
The diphenylbutylpiperidines are structurally related to the piperidinobutyrophe-
nones. They are relatively selective for the D2 receptors and do not interact with
histaminergic receptors [71. In addition, these neuroleptics are able to block voltage-
dependent calcium channels [49].
Fluspirilene [1841-19-6], 8-[4,4-bis(4-fluorophenyl)butyl]-l-phenyl-l,3,8-triaza-

spiro[4.5]-decan-4-one, C29H31F2N3O, M, 475.59, mp 187-190 °C is prepared by con
densing a spirobicyclic amine with the reievant brominated diphenylbutane derivative.
600
N e u ro le p tic s
The spiro compound is prepared from cyclohexanone via an aminonitrile (Strecker
synthesis) [50].
Fluspirilene bears the same side chain as spiperone (see Section 2.3). The deep
intramuscular injection of a microcrystalline suspension of fluspirilene results in a long
duration of action (ca. one week).
Trade Names: Imap (Janssen), Redeptin (SKF, UK).
Penfluridol [26864-56-2], l-[4,4-bis(4-fluorophenyl)butyl]-4-(4-chloro-3-trifluoro-

methylphenyl)-4-hydroxypiperidine, C28H27CIF5NO, Mr 523.99, mp 105-107 °C, is
obtained by reducing the ketone of 3-(4-fluorobenzoyl)propionic acid into a lactone.
Alkylation of fluorobenzene with this lactone under Friedel - Crafts conditions yields a
diarylbutyric acid, which is converted into an amide and reduced to the amine; for
details of synthesis see [51].
F Cl
Trade Names: Cyperon (Esteve, Spain), Fluidol (Janssen), Longoran (Isis, Yugoslavia), Micefal (Spofa,
Czechoslovakia).
Pimozide [2062-78-4], l-{l-[4,4-bis(4-fluorophenyl)butyl]-4-piperidinyl}-2-benz-

imidazolinone, C28H29F2N3O, Mr 461.56, mp 214-218 °C. Ring opening of diphenylcy-
clopropyicarbinol gives a homoallylic chloride which is hydrogenated and then con
densed with the relevant benzimidazolinone derivative [52]. The side chain is identical
to that of benperidol(see p. 347).
601
Pimozide is used for the treatment of acute and chronic schizophrenia and also in
management of Gilles de la Tourette's syndrome.
Trade Names: Antalon (Arzneimittelwerk Dresden, Germany), Opiran (Roussel, France), Oralep (Abie,
Israel), Orap (Janssen), Pimotid (Medica, Finland), Pirium (Janssen)
2.5. Dibenzazepines and Analogues

This class of drugs includes tricyclic compounds with seven-membered central rings.
Clozapine was the first neuroleptic that seldom showed extrapyramidal side effects and
was therefore termed an “atypical” neuroleptic.
Two subclasses can be distinguished;
1) The seven-membered ring is an azepine having a piperidinoalkyl chain on its

nitrogen atom (carpipramine and clocapramine)
2) The basic substituent (a N-methylpiperazine) is attached to the imino bridge
X = NH, s, o
Structural variations in this series of compounds led to the development of classical

neuroleptics (clothiapine, loxapine, and clozapine) and hypnotics (perlapine).
602
N e u ro le p tic s
2.5.1. Dibenzazepines
The dibenzazepine derivatives are prepared by the following general method: The
tricyclic nitrogen atom is alkylated with a 1,3-dihalogenated propane, the resulting
monohalogeno compound is then condensed with the piperidine derivative:
Carpipramine [5942-95-0], 5-[3-(4-piperidino-4- carbamoylpiperidino)propyl]-10,ll-

dihydro-5//-dibenz[^,/]azepine, C28H38N4O, M, 446.64, mp 260 “C, for preparation see
[53]. The compound is a S-HTa antagonist. This could explain its clinical efficacy in
symptoms like asthenia, anxiety, and social withdrawal.
Trade Names: Defekton (Yoshitomi, Japan), Prazinil (Fournier, France).
Clocapramine [47739-98-0], 5-{[3-(4-carbamoyl-4-piperidino]propyl}-3-chloro-10,ll-

dihydro-5//-dibenz[Z7,/]azepine dihydrochloride monohydrate, C28H41CI3N4O2, M,
572.0, mp 267°C is a chlorinated derivative of carpipramine with a bitter taste; for
preparation see [53].
Trade Name: Clofekton (Yoshitomi, Japan).
603
2.5.2. Piperazinyl Derivatives
Dibenzazepine analogues are prepared by two main routes (Fig. 1). In the first one,
the lactam function of the tricycle is activated as an imino chloride (A) or a thioether
(B), which is then condensed with A-methyl piperazine. In the second route, the imino
bridge of the tricycle is formed by dehydration of an urea function (C) or condensation
of an amine and an amide function (D).
Figure 1. Synthesis of benzazepine

analogues
P,S,
(CH3)3C0K j CICHjCjHjjNOj
CH,
/—\ N
H,C-N N-H /HjC-N n-h
\__ /
H3PO,
or
POCl p,s.
©
CH, CH,
N-
0=<
Clothiapine \205S-52-S\, 2- chloro-ll-(4-methyl-l-piperazinyl)-dibenzo[Z>,/] [l,4]thia-

zepine, C18H18CIN3S, 343.89, mp 118-120 °C, for preparation see [541.
Trade Names: Deliton (Dainippon, Japan), Entumine, Etomine, Etumina, Etumine (Sandoz Wander).
Clozapine [5786-21-0], 8- chloro-ll-(4-methyl-l-piperazinyl)-5//-dibenzo[^,c][l,4]-

diazepine, C18H19CIN4, Mr 326.83, mp 183-184 °C, for preparation see [55].
604
N e u ro le p tic s
Despite severe hematologic side effects (agranulocytosis), this compound is used to
treat otherwise irresponsive patients. Clozapine has one order of magnitude higher
affinity for the D4 receptors than for D2 receptors [56].
CH
Trade Names: Alemoxan (Arzneimittelwerk Dresden, Germany), Clozaril (Sandoz Wander, UK), Le-
ponex (Sandoz Wander).
Loxapine [1977-10-2], 2- chloro-ll-(4-methyl-l-piperazinyl)-dibenz[Z;,/][l,4]oxazepine,

CisHigClNsO, Mr 327.81, mp 109-110 °C, for preparation see [57].
CH.
Trade Names: Daxolin (Dome, USA); Desconex (Lafarquim, Spain); Loxapac, Loxitane (Lederle).
2.6. Benzamides
The benzamide neuroleptics are selective blockers of D2 receptors and are therefore
free of the side effects arising from interactions with other receptors. Sulpiride, the most
important member of this class, was recognized as an “atypical” neuroleptic [58]. It
exhibits a specific action on the mesolimbic dopamine system [59].
Sulpiride [15676-16-1], Ar-[(l-ethyl-2-pyrrolidinyl)methyl]-2-methoxy-5-sulfamoyl-

benzamide, C15H23N3O4S, Mr 341.43, mp 175-182 “C, is prepared by reaction of 2-
aminomethyl-1-ethyl-pyrrolidine with phosphorus trichloride, followed by the conden
sation of the intermediate with 5-sulfamoyl-2-methoxybenzoic acid [60].
605
Trade Names: Abilit (Sumitomo, Japan), Aiglonyl (Fu-mouze, France), Arminol (Krewel, Germany),
Azugastan (Kobayashi, Japan), Betamac, Dixibon (Sandoz, Switzerland), Dobren (Ravizza, Italy),
Dogmatil (Delagrange, France), Dolmatil (Squibb), Equilid (Merrell Dow), Levopraid (Ravizza, Italy),
Miradol (Mitsui, Japan), Mirbanil (Boehringer, Germany), Neuromyfar (Emifar, Spain), Sulpril (Astra),
Tohpiride (Toyo Pharma, Japan).
Sultopride [53583-79-2], AJ-[(l-ethyl-2-pyrro-lidinyl)methyl]-5-(ethylsulfonyl)-2-

methoxybenz-amide, C17H26N2O4S, Mr 354.47, mp 181 -182 °C, is related to sulpiride
and is prepared analogously 1601.
Trade Names: Barnetil (Delagrange, France), Barnotil (Vita, Italy), Topral (Alkaloid, Yugoslavia).
Tiapride [51012-32-9], Al-[2-(diethylamino)-ethyl]-2-methoxy-5-(methylsulfonyl)benz-

amide, C15H24N2O4S, Mr 328.43, mp 123 -125 °C, is prepared by activating 2-methoxy-5-
(methylsulfonyl)benzoic acid with ethyl chloroformate and reacting the mixed anhydride
with 2-(diethylamino)ethylamine [611.
N(CH2CH3)^
H,C
Trade Names: Delpral (Bender, Austria), Equilum (Fumouze, France), Gramalil (Fujisawa, Japan),
Luxoben (Chinoin, Italy), Porfanil (Prodes, Spain), Tiaprizal (Delagrange, France).
606
Amisulpride [71675-85-9], 4-amino-A/-[(l-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfo-
N e u ro le p tic s
nyl)-2-methoxybenzamide, C17H27N3O4S, Mj- 369.48, mp 126 -127 °C, is prepared in an
analogous way to tiaprides. 2-Aminomethyl-l-ethylpyrrolidine is condensed with the
appropriate benzoic acid derivative in the presence of ethyl chloroformate [62] or with
a benzoyl chloride derivative. In the latter case, the aromatic ring bears a nitro group
which is then reduced [63]. Amisulpride is used against both negative and productive
symptoms of schizophrenia.
rAr°"cmCH3
HsC-n
O ''
b NH3
Trade Name: Solian (Delagrange, France).
Remoxipride [80125-14-0], (,S)-3-bromo-2,6-dimethoxy-iV-(l-ethyl-2-pyrrolidinyl)-

methyll-benzamide, CieHasBrNaOs, M, 371.23, mp 184-185 T, is prepared by con
densing the appropriate benzoyl chloride derivative with the optically active l-ethyl-2-
(aminomethyl)pyrrolidine [64]. Like sulpiride, remoxipride seems to have a specific
action on the mesolimbic dopaminergic system and a lower impact on the striatal
dopaminergic system, therefore generating less extrapyramidal side effects [65].
H,C
Trade Name: Roxiam (Astra, Denmark).
Clebopride [55905-53-8], 4-amino-AT-(l-benzyl-4-piperidyl)-5- chloro-2-methoxyben-

zamide, C20H24CIN3O2, M, 389.88, mp 194-195 T, for preparation see [66].
Trade Names: Clanzol (Orfi, Spain), Clebon (Wyeth), Cleboril (Almirall, Spain), Vuxolin (Carlo Erba).
Metoclopramide [ 364-62-5 ], 4-amino-5- chloro-A(-[2-(diethylamino)ethyl]-2-meth-

oxybenzamide, C14H22CIN3O2, 299.81, mp 146-148 T, is widely used as an
antiemetic; for preparation see [67].
607
H
N(CH,CH,),
Cl
Trade Names: Cerucal (Arzneimittelwerk Dresden, Germany), Duraclamid (Durachemie, Germany),

Elieten (Nippon Kagaku, Japan), Emex (Beecham), Gastrese LA (Robins, USA), Gastromax (Earmitalia,
Italy), Maxeran (Delagrange, France), Maxolon (Beecham), Meclopran (Lagap, Switzerland), Metramid
(Nicholas), Moriperan (Morishita, Japan).
[66644-81-3], AJ-[(l-allyl-2-pyrrolidinyl)methyl]-5-sulfamoyl-5-veratra-
Veralipride
mide, C17H25N3O5S, 383.5, for preparation see [68]. It is also used to treat
menopausal disorders.
o
Trade Names: Accional (Fides, Spain), Agradil (Vita, Italy), Agreal (Delagrange, France), Faltium
(Erodes, Spain), Verapril (Midy, Italy).
2.7. Miscellaneous Neuroleptics

Molindone [7416-34-4], 3-ethyl-2-methyl-5-(morpholinomethyl)-4,5,6,7-tetrahydro-
l//-indol-4-one, C16H24N2O2, 276.37, mp 180-181 °C, is prepared in two steps.
Condensation of cyclohexane-1,2-dione with a keto-oxime affords the indolic ring
system. Mannich condensation with morpholine completes the synthesis [69].
HO H
o
Trade Names: Lidone (Abbott), Moban (Endo, USA).
608
Oxipertine [153-87-7], 5,6-dimethoxy-2-methyl-3-[2-(4-phenyl-l-piperazinyl)ethyl]in-
N e u ro le p tic s
dole, C23H29N3O2, Mr 379.5, mp 250-252 °C, is prepared by condensation of an
indoleacetic acid derivative with AT-phenyl-piperazine, followed by reduction [701.
H
1
Trade Names: Equipertine (Sterling, Belgium), Forit (Winthrop, Switzerland), Integrin (Sterling, UK),
Opertil (Winthrop, Denmark).
2.8. Neuroleptics Under Development

Novel strategies for the treatment of schizophrenia have arisen from the recognition
of the possible benefits from additional antagonism at neurotransmitter receptors other
than those for dopamine. Thus, several drugs under development act at multiple
receptors [711. Risperidone [106266-06-2] (R-64 766, Janssen) is a benzisoxazole deriva
tive with mixed D2/5-HT2 blocking properties; it is reported to improve negative signs
of schizophrenia accompanied with only few motor side effects. Amperozide [75558-90-
6] (FG-5606, Kabi), 10204,636 [111374-72-2], and HP 873 [133454-47-4] (Hoechst) are
other drugs showing high affinity for 5-HT2 receptors currently undergoing clinical
investigation for schizophrenia. Org-5222 [85650-56-2] (Organon) is active on a range of
receptors including Di, D2, oci, CZ2> 5-HT2, and receptors; it also antagonizes
dopaminomimetics in rodents [72]. Drugs acting at 5-HT3 receptors have potential
interest as antipsychotics [73], e.g., drolasetron [115956-13-3] (MDL-73147, Marion
Merrell Dow) and zacopride [90182-92-6] (AHR-11190, American Home Products). Most
neurotransmitters are subject to a negative-feedback control by presynaptic autorecep
tors that prevent further release by activating channels and/or inhibiting Ca ^
channels. Thus the stimulation of presynaptic receptors induces inhibition of trans
mitter release. Dopaminergic activity can be reduced not only by postsynaptic receptor
antagonism, but also by activation of presynaptic autoreceptors. Roxindole [112192-04-8]
(EMD-49980, E. Merck) and CGS-15873 [118929-49-0] (Ciba-Geigy) [74] mimick this
feedback inhibition mechanism for endogenous dopamine; they have an antipsychotic-
like pharmacological profile. Other antipsychotics under development include antiag
gression drugs such as eltoprazine [98224-03-4] (DU-28853, Solvay), and the glycine
prodrug milacemide [76990-56-2] (CP-15525, Monsanto), which also has antidepressant
and cognitive-enhancing potential. Other compounds act as specific D2- or Di-receptor
antagonists (for recent review, see [75]).
609
3. Antidepressants
Depression corresponds to major modifications of mood and is characterized by
affective disorders that extend outside acceptable limits and impair thinking and
perception. Most depressive patients suffer only from unipolar or major depression.
In others, depression is associated with intermittent episodes of mania (manic-depres
sive illness). Major depression is characterized by sadness, despair, self-depreciation,
insomnia, anorexia, and also sometimes suicidal behavior. Manic-depressive illness is
characterized by dysphoria, irritability, marked insomnia, impaired judgement, or
behavior. Major depression and manic-depressive illness appear to react to different
treatments.
Treatment of depression was first based on the sedative effect of opium (laudanum)
or on the psychostimulant activity of amphetamines. At the end of the 1950s, Kuhn
discovered that imipramine, a dibenzazepine derivative first tested for its antipsychotic
and antihistaminic properties, was a powerful antidepressive agent in clinical trials
176]. Simultaneously, Kline successfully used iproniazide, an isoniazide derivative used
as a drug against tuberculosis, in the treatment of depression 177]. The discovery of
imipramine stimulated the search for related compounds based on the tricyclic diben
zazepine structure. Iproniazide was found to be an irreversible inhibitor of monoamine
oxidase, a result which also stimulated further research.
3.1. Tricyclic Antidepressants

Tricyclic antidepressants have been widely used as the drugs of choice for the
treatment of major depression. In behavioral studies in rodents, tricyclics depress
spontaneous motor ac-tivity and impair the acquisition and performance of a condi
tioned avoidance test. Their best recognized psychopharmacological characteristic
corresponds to their interaction with reserpine and tetrabenazine which deplete bio
genic amines in the brain. The tests used most frequently to predict the antidepressant
effect of a drug are based on the inhibition of sedation, catalepsy, hypothermia, or
ptosis in rodents pretreated with reserpine 178]. In electroencephalographic (EEG)
studies, low doses induce synchronization which reflects sedative activity; high doses
produce a desynchronized EEG and are sometimes able to induce EEG epileptogenic
events 179], 180]. Moreover, in sleep-wakefulness studies, these drugs often increase
slow-wave sleep and decrease paradoxical sleep.
Under normal conditions neurotransmitters in the synapse are taken up by the cell.
Uptake inhibitors bind to specific sites and impede physiological uptake; neurotrans
mitters (NA, DA, or 5-HT) thus show higher concentrations for longer in the synaptic
cleft and induce more intense neuronal activity. In contrast an enhancer of 5-HT uptake
increases the physiological uptake of the transmitter and thus decreases its synaptic
concentration.
610
A n tid e p re s s a n ts
Tricyclic antidepressants potentiate the action of biogenic amines [mainly noradrena
line (NA) and serotonin (5-hydroxytryptamine, 5-HT)] by inhibiting their presynaptic
uptake after release which leads to increased concentrations of these neurotransmitters
at the synapse. None of the compounds in this series are purely selective inhibitors for
NA or 5-HT uptake [81], [82]. For example, desipramine is most active in blocking NA
uptake and has a low efficacy on 5-HT uptake, while amitriptyline is equipotent in
blocking both NA and 5-HT uptake.
3.1.1. Inhibitors of Noradrenaline and/or

Serotonin Uptake
Amitriptyline [50-48-6], 10,ll-dihydro-5-(3-dimethylaminopropylidene)-5//-diben-
zo[fl,^/]cycloheptene, C20H23N, M, 277.39, hydrochloride mp 196-197 °C; this com
pound can be prepared by reaction of 5-oxo-10,ll-dihydro-5//-dibenzo[fl,<f]cyclohep-
tene with the Grignard reagent of 3-dimethylaminopropyl chloride followed by dehy
dration of the resulting tertiary alcohol in a strongly acidic medium [83]-[85].
Amitriptyline and other tricyclic antidepressants are particularly effective in the treat
ment of endogeneous depressions, but are less effective in reactive depression.
Trade Names: (Hydrochloride) Adepril (Merrell Dow Lepetit), Amitid (Squibb), Amitril (Warner-
Chilcott), Endep, Laroxyl (Roche), Lentizol (Warner-Lambert, Parke Davis), Saroten (Lundbeck,
Denmark, Tropon, Germany), Sylvemid (Weiner, Germany), Elavil, Tryptanol, Tryptizol (Merck Sharp
& Dohme).
Amoxapine [14028-44-5], 2-chloro-ll-(l-piperazinyc)dibenz[^,/j [l,4]oxazepine,

C17H16CIN3O, Mr 313.79, mp 175-176 T. Treatment of the starting lactam with
phosphorus oxychloride, followed by condensation of the corresponding imidochloride
with piperazine affords amoxapine [57].
611
Amoxapine is a tricyclic antidepressant with actions and uses similar to those of

amitriptyline [86].
Trade Names: Asendin, Asendis, Defenyl, Demolox, Moxadil, Omnipress (Lederle).
Clomipramine [303-49-1], 3-chloro-10,ll-dihydro-5-(3-dimethylaminopropyl)-5//-

dibenz-[i>,/]azepine, C19H23CIN2, 314.87, hp (0.04 kPa) 160-170T, hydrochloride
mp 189-190 °C. The synthesis of clomipramine is as follows [87]:
CH,OH
Cl
HI H
1) NaNHj
2) BrCH,(CHJ,N(CH,),'
I
CH3
Clomipramine is particulary effective in patients with obsessive - compulsive disor
ders.
Trade Names: (Hydrochloride) Anafranil (Geigy), Hydiphen (Arzneimittelwerk Dresden, Germany),

Maronil (Unipharm, Israel).
Dosulepin [113-53-1], Dothiepin, 6,ll-dihydro-ll-(3-dimethylaminopropylidene)di-

benzo-[A,c]thiepin, C19H21NS, M, 295.45, bp (0.006 kPa) 171-172 T, mp 55-57T,
hydrochloride mp 218-221 °C. The synthesis of dosulepin follows [88]:
612
A n tid e p re ssa n ts
Trade Names: (Hydrochloride) Idom (Kanoldt, Germany), Prothiaden (Boots; Boots Dacour, France;
Spofa, Czechoslovakia), Xerenal (Kwizda, Austria).
Doxepin [1668-19-5], 6,ll-dihydro-ll-(3-dimethylaminopropylidene)dibenz[b,e]oxe-

pin, C19H21NO, Mr 279.37, bp (0.026 kPa) 260-270 T, hydrochloride mp 188-189 T.
This dibenz[Z;,c]oxepin can be considered as an analogue of amitriptyline (replacement
of methylene group by an oxygen atom). The synthesis of doxepin is summarized below
[891.
Trade Names: (Hydrochloride) Adapin (Pennwalt, USA), Aponal (Galenus, Germany), Novoxapin
(Ester, Spain), Quitaxon (Boehringer Mannheim, Erco Denmark), Sinequan (Pfizer-Roerig).
Imipramine [50-49-7], 10,ll-dihydro-5-(3-dimethylaminopropyl)-5/f-dibenz[Z?,/]-

azepine, C19H24N2, M, 280.40, bp (0.013 kPa) 160 °C, hydrochloride mp 174-75T.
Imipramine is prepared by alkylation of 10,lTdihydro-5//-dibenz[^,/lazepine, which is
the tricyclic parent structure for a range of psychopharmaceuticals, with 3-dimethyl-
aminopropyl chloride in the presence of sodamide [90]:
613
MQ.
C
< The starting material can be obtained by oxidative dimerization of 2-nitrotoluene to
give l,2-bis-(2-nitrophenyl)ethane which is hydrogenated to give the corresponding
diamine. Ring closure takes place on heating with elimination of ammonia to afford
the parent dibenzazepine.
Imipramine is a tricyclic antidepressant with a similar mode of action and similar
uses as amitriptyline but with less marked sedative properties.
Trade Names: (Hydrochloride) Chrytemin (Fujinaga, Japan), Deprinol (Dumex, Denmark), Efliranol
(Pfizer), Feinalmin (Sanko, Japan), Imavate (Robins, USA), Janimine (Abbott), Melipramin (Egis,
Hungary), Presamine (USV, USA).
Desiprami ne [50-47-5], 10, ll-dihydro-5-13-(methylaminopropyl)-5//-dibenz [h,f]-

azepine, C18H22N2, M, 266.37, bp (0.002 kPa) 172-174 T, hydrochloride
mp 214-218 °C. Treatment of imipramine with ethyl chloroformate followed by alka
line hydrolysis affords desipramine in high yield 1911.
HI
Trade Names: (Hydrochloride) Norpolake (Lakeside, USA), Norpramin (Merrell Dow Pharmaceuti
cals), Nortimil (Chiesi, Italy), Pertofran, Sertofren (Geigy).
Lofepramine [23047-25-8], Ar-methyl-AL(4- chlorobenzoylmethyl)-3-(10,ll-dihydro-

5if-dibenzol/?,/lazepin-5-yl)propylamine, C26H27CIN2O, M, 418.97, mp 104-106 T,
hydrochloride mp 152 —154 °C. Lofepramine is obtained by reaction of desipramine
with 4'-chloro-bromoacetophenone 1911.
Trade Names: (Hydrochloride) Deftan, Deprimil, Emdalen, Gamanil, Gamonil (E. Merck, Germany),
Tymelyt (Leo, Sweden).
614
Metapramine [21730-16-5], 10,ll-dihydro-5-methyl-10-(methylamino)-5H-dibenz-
[Z?,/]azepine, C16H18N2, Mj. 238.33, hydrochloride mp 238-240 °C. This compound
can be prepared in two ways [92];
Trade Name: Timaxel (Specia, France).
Nortriptyline [72-69-5], 10,ll-dihydro-5-(3-methylaminopropylidene)-5//-dibenzo-

[fl,J]cycloheptene, C19H21N, Mr 263.37, hydrochloride mp 213-215 °C. This compound
is prepared as follows [93].
Trade Names: (Hydrochloride) Acetexa (Lilly), Allegron (Dista), Altilev (Squibb), Nortrilen (Lundbeck,
Denmark, Tropon, Germany), Nortrilen (Lilly, Sandoz-Wander), Sensival (Pharmacia, Sweden), Vividyl
(Lilly).
Protri pty li ne [438-60-8], 5-(3-methylaminopropyl)-5H-dibenzo [fl, d] cycloheptene,

C19H21N, Mr 263.37, hydrochloride mp 169-171 °C. Protriptyline can be prepared
as follows [94]:
615
X {CH3),N.^^^MgCl
Cl CH,
'N'
CH,
1) BrCN
2) CH3COOH/HC
,CH
'N'
H
Protriptyline has considerably less marked sedative properties than amitriptyline,

and may have stimulant effects.
Trade Names: (Hydrochloride) Concordin, Vivactil (Merck Sharp & Dohme), Maximed (Frosst, Ger
many, Merck Sharp & Dohme), Triptil (Merck-Frosst, Pointe Claire Dorval, Canada, Merck Sharp &
Dohme).
Butriptyline [35941-65-2], 10,ll-dihydro-5-(3-dimethylamino-2-methylpropyl)-5//-

dibenzo-[a,cf]cycloheptene, C21H27N, M, 293.46, hp (0.133 kPa) 180-185 T, hydro
chloride mp 188 -190 °C. The intermediate olefinic compound is prepared analogously
to the amitriptyline parent olefin (see p. 611), and finally reduced with LiAlH4 [95].
CH, CH.
Trade Names: Centrelyse, Evadene (Ayerst), Evadyne (Ayerst), Evasidol (Arcana, Austria).
Quinupramine [31721-17-2], 10,ll-dihydro-5-(3-quinuclidinyl)-5//-dibenz[Zi,/]aze-

pine, C21H24N2, Mr 304.43, hydrochloride mp 150 °C, is prepared as follows [961:
Trade Names: Kevopril (Rhone-Poulenc), Kinupril (Pharmuka, France), Quinuprine (Rhone, Spain).
616
3.1.2. Enhancers of Uptake
Tianeptine [66981-73-5], 7-[(3- chloro-6,ll-dihydro-6-methyldibenzo[c,/][l,2]thiaze-
pin-ll-yl)amino]heptanoic acid 5,5-dioxide, C21H25CIN2O4S, 436.95, sodium salt mp
180 °C. Tianeptine is prepared as follows [97]:
Tianeptine is used in the treatment of reactive and neurotic depression, as well as in

the treatment of anxious states.
Trade Name: Stablon (Ardix, France).
3.1.3. Inhibitors of Dopamine Uptake

Amineptine [57574-09-1], 7-[(10,ll-dihydro-5//-dibenzolfl,J]cyclohepten-5-yl)ami-
nolheptanoic acid, C22H27NO2, 337.47, hydrochloride mp 226-230 °C, is prepared
as follows [98]:
1) HjN(CHj),C00CH2CH3
2) NaOH
Trade Names: Directim, Neolior, Viaspera (Servier, France), Maneon (Poli, Italy), Provector (Servier,
Euthe-rapie, France).
3.1.4. Other Tricyclic Antidepressants

Carpipramlne [5942-95-0], 5-{3-[4-carbamoyl-4-piperidino)piperidino]propyl}-
10,ll-dihydro-5//-dibenz[Z;,/]azepine, also has neuroleptic properties (see Section
2.5.1).
617
[24701-51-7], 5//-dibenzo[a,^/]cydohepten-5-one, 0-[2-(methyl-
A n tip sy c h o tic s/N e u ro ie p tic s

Demexiptiline
amino)-ethyl]oxime, CigHigNaO, 278.35, hydrochloride mp 232-233 °C. Demex
iptiline is prepared as follows [99]:
Trade Name: Deparon (Aron, France).
Dibenzepin [4498-32-2], 10,ll-dihydro-10-(2-dimethylaminoethyl)-5-methyl-ll-oxo-

dibenzo[^,c][l,4]diazepine, C18H21N3O, 295.37 mp 116-117 °C, hydrochloride mp
238 °C. Dibenzepin is prepared as follows [100]:
I
CH,
Trade Names: Ecatril, Neodit (Sandoz-Wander).
Noxiptilin [3362-45-6], 10,ll-dihydro-5//-dibenzo[f?,J]cyclohepten-5-one, 0-[2-(di-

methylamino)ethyl]oxime, C19H22N2O, 294.4, bp (0.006 kPa) 160-164 °C, hydro
chloride mp 185-187 °C. Noxiptilin is prepared as follows [101];
618
Trade Names: Agedal (Bayer), Nogedal (Theraplix, France), Sipcar (Bernabo, Argentina).
Opipramol [315-72-0], 4-[3-(5//-dibenz[Z?,/]-azepin-5-yl)propyl]-l-(2-hydroxyethyl)-

piperazine, C23H29N3O, Mr 363.49, mp 100-101 °C, dihydrochloride mp 228-230 °C.
Opipramol is prepared as follows [102]:
HO-(CHj)3-N N-(CHj)30C0CH3
—ÔCOCHj
1) Cu, heat
2) KOH
Trade Names: Deprenil (Yurtoglu, Turkey), Dinsidon, Ensidon, Insidon, Nisidana (Geigy).
Propizepine [10321-12-7], 6,ll-dihydro-6-[2-(dimethylamino)propyl-5/f-pyrido[2,3-

Z>][l,5]-benzodiazepin-5-one, C17H20N4O, Mr 296.38, mp 122 °C, hydrochloride, mp
235 T [103].
619
Trade Names: Depressin, Vagran (UPSA, France).
Trimipramine [739-71-9], 10,ll-dihydro-5-[3-(dimethylamino)-2-methylpropyl]-5//-

dibenz[Z>,/]azepine, C20H26N2, 294.42, mp 45 °C, maleate salt mp 142 °C. The
shortest synthesis of trimipramine is shown below [1041:
Trade Names: Surmontil (Specia, May & Baker, Farmitalia Carlo Erba), Stangyl (Rhone-Poulenc).
3.2. Tetracyclic Antidepressants

Maprotiline and mianserin constitute a second generation of antidepressants that are
chemically characterized by a tetracyclic structure. In animal models, maprotiline, a
dibenzobicyclooctadiene derivative, has a sedative and tranquilizing activity [105].
Clinical studies have demonstrated its activity to be equivalent to that of the tricyclic
antidepressants [106], but with less cardiac side effects. Maprotiline has a potent
activity in blocking NA uptake without effect on 5-HT uptake [105].
Mianserin is a tetracychc piperazinoazepine first developed as an antihistamine and
anti-5-HT drug. It has antidepressant activity in humans and induces drowsiness during
the first weeks of treatment; its possible cardiotoxic effects are less marked than those
observed with tricyclic antidepressants [107]. Mianserin is a potent inhibitor of H2-
receptor-mediated adenylate cyclase formation in brain [108] and has a presynaptic a-
adrenoreceptor blocking effect [109]. Its mechanism of action appears to involve release
of NA via cortical a2-adrenergic autoreceptor blockade.
Maprotiline [10262-69-8], l-(3-methylaminopropyl)dibenzo[Z?, c]bicyclo[2.2.2]octa-

diene, C20H23N, 277.41, mp 92-94T, hydrochloride mp 230-232 °C. Maprotiline
is prepared as follows [110]:
620
r
o o
Maprotiline differs structurally from tricyclics due to the presence of an additional

alicyclic bridge. It resembles amitriptyline with regard to both efficacy and side effects.
It may have proconvulsant properties.
Trade Name: Ludiomil (Ciba).
Mianserin [24219-97-4], 2-methyl-l,2,3,4,10,14Z>-hexahydro-2//-pyrazinoIl,2/lmor-

phanthridine, C18H20N2, Mr 264.37, hydrochloride mp 282-284 °C. Mianserin is
prepared as follows 11111:
H,C
\
NH
Mianserin does not display significant antimuscarinic properties, but has a marked
sedative action.
Trade Names: Athymil, Bolvidon, Lantanon, Tetramide, Tolvin, Tolvon (Organon).
621
3.3. Monoamine Oxidase Inhibitors
(MAOl)
Low single doses of MAOI produce only minor or negligible changes in animal
behavioral pharmacology even when a significant increase in biogenic amines is mea
sured in the brain. Nevertheless, combined with other agents such as reserpine or
tetrabenazine (which induce biogenic amine depletion), they tend to produce excite
ment rather than sedation in rodents. MAOI have only slight effects on EEC recordings,
with the exception of tranylcypromine which is a psychostimulant. They are amongst
the most effective drugs in suppressing paradoxical (rapid eye movement, REM) sleep
in humans and are used in narcolepsy for this reason.
Monoamine oxidase (MAO) is a complex enzyme which is responsible for the
metabolic degradation of biogenic amines. Drugs which inhibit this enzyme system
therefore induce an increase in the concentration of biogenic amines such as adrenaline,
NA and 5-HT which explains their antidepressant effect 11121. MAO occurs in two
forms that differ in their preferences for substrates and sensitivities to selective in
hibitors : MAO-A preferentially acts on NA and 5-HT in humans and MAO-B acts on
phenethylamine, methylhistamine, and dopamine (DA). Irreversible MAOIs bind cova
lently to the enzyme, involving noncompetitive inhibition. Recovery of MAO activity is
only achieved by arrival of newly synthesized enzyme. Reversible MAOIs form a less
stable bond with the enzyme and they can be removed from their binding site, MAO
activity therefore recovers.
3.3.1. Hydrazine Derivatives

Benmoxine [7654-03-7], benzoic acid 2-(l-phenylethyl)hyrazide, C15H16N2O, Mr
240.29, mp 93 - 94 °C. Hydrogenation of the hydrazone obtained by condensation of
acetophenone with benzoylhydrazine affords benmoxine 11131.
Trade Names: Nerusil (Iquinosa, Spain); Neuralex (Millot, France).
Iproclozide [3544-35-2], (4-chlorophenoxy)-acetic acid 2-isopropylhydrazide,

C11H15CIN2O2, Mr 242.72, mp 93-94°C. Iproclozide is prepared as follows [1141:
622
o
OCHjCHj
Cl
O
HjNNH,
---------> Ci>^
I I I
H
O ?
1) CH3COCH3
2) KBH^ ^ H
Trade Name: Sursum (Merrell Dow Pharmaceuticals, Ibsa, Switzerland).
Iproniazid [54-92-2], isonicotinic 2-isopropylhydrazide, C9H13N3O, Mr 179.22, mp

112.5-113.5 °C, can be prepared using the synthetic pathway described for iproclozide
[115]. An alternative synthesis is described in [116].
Trade Names: Ipronid (Afi, Norway), Marsilid (Roche).
Isocarboxazid [59-63-2], 5-methy]-3-isoxazo]ecarboxylic acid 2-benzyihydrazide,

C12H13N3O2, Mr 231.25, mp 105-106 °C. Isocarboxazid is prepared according to the
following scheme [117]:
o-N H
H,c iX A 1) Benzaldehyde
T NH3 2) NaBH„
H3C
Trade Names: Marplan, Marplon (Roche).
Nialamide [51-12-7], isonicotinic acid 2-(2-benzy]carbamoylethy])hydrazide,

C16H18N4O2, Mr 298.34, mp 152-153 “C [118].
Trade Names: Espril (Saba, Turkey), Niamide (Pfizer-Roerig), Nuredal (Egis, Hungary), Surgex (Firma,
Italy).
623
Phenelzine [51-71-8], phenethylhydrazine, CgHi2N2, 136.19, bp (0.013 kPa)

74 °C, hydrochloride mp 174 °C, for preparation see [119].
Trade Names: (Acid sulfate) Nardelzine (Substancia, the Netherlands, Substancia-Parke Davis, Spain,
Warner-Chilcott), Nardil (Warner-Chilcott, Parke-Davis).
3.3.2. Nonhydrazine Derivatives

Caroxazone [18464-39-6], 2-oxo-l,3-benzoxazine-3(4H)-acetamide, C10H10N2O3, Mj
206.20, mp 203-205 °C. Caroxazone is prepared as follows [120]:
1) NaOH
2) NHj, dicyclohexylcarbodiimide
Trade Name: Timostenil (Farmifalia Carlo Erba,Italy).
Milacemide [76990-56-2], 2-pentylaminoacetamide, C7H16N2O, Mj. 144.14, mp

46 °C, is prepared by condensation of pentylamine with chloroacetamide [121].
.NH,
Trade Names: Glyzac, Glyzan (Searle).
Pargyline [555-57-7], N-methyl-Ar-2-propynylbenzylamine, C11H13N, Mj. 159.22, hy

drochloride mp 154-155 °C, is prepared by condensation of propynyl bromide with
benzylmethylamine [122].
Pargyline is also an antihypertensive agent.
Trade Names: Eudatine, Eutonyl (Abbott).
624
Selegiline [14611-51-9], (/?)-Ar,a-dimethyl-Ar-2-propynylphenethylamine, C13H17N, Mj.
187.14, bp (0.08 kPa) 92-93°C, hydrochloride mp 141.0-141.5 °C. Selegiline can be
prepared according to various schemes, the shortest is shown below [123]:
H NHCH3
Selegiline is used in the treatment of Parkinson's disease.
Trade Names: Eldeprine (Unicet, France), Jumex (Chinoin, Hungary, Chiesi, Italy), Jumexal (Labatec,
Switzerland), Movergan (Asta-Degussa, Germany, Astra).
Tranylcypromine [155-09-9], tra«s-(±)-2-phenylcyclopropylamine, CgHuN, M,

133.19, bp (0.20-0.213 kPa) 79-SOT, hydrochloride mp 164-166T; for prepara
tion, see [124].
NHj
Tranylcypromine is used for the treatment of adult outpatients with reactive depression.
Trade Names: (Sulfate salt) Parnate (Smith Kline & French, Rohm Pharma, Germany), Transapin
(Medexport, Independent Estates Community), Tylciprine (Theraplix, France).
3.3.3. Reversible MAO-A Inhibitors

Metralindole [54188-38-4], 3-methyl-8-methoxy-3//-l,2,5,6-tetrahydropyrazino-
[l,2,3flM-j5-carboline, C15H17N3O, M, 255.14, mp 164-166 T. Metralindole is prepared
as follows [125]:
men,).
Trade Name: (Sulfate salt) Incazan (Independent Estates Community).
Moclobemide [71320-77-9], 4-chloro-Ar-(2-morpholinoethyl)benzamide,

C13H17CIN2O2, Mr 268.7, mp 137 T. Various syntheses are described for moclobemide.
625
cur Figure 2. Synthesis of pirlindole
CH
0(CH,)3CH3
J^Hj/Raney Ni
k^NH
the simplest and shortest being the reaction of 4- chlorobenzoyl chloride with N-(2-
aminoethyl)morpholine in pyridine [126].
Trade Name: Auroxix (Roche, Switzerland).
Pirlindole [60762-57-4], 8-methyl-l,2,3,4-tetrahydro-l,10-trimethylenepyrazino-

[l,2-a]indole, Ci5HigN2, 226.14, hydrochloride, mp 260—261 °C. It can be prepared
in two ways (Fig. 2) [127].
Trade Names: Lifril (Casen Fisons, Spain), Pyrazidol (Independent Estates Community).
Toloxatone [29218-27-7], 5-(hydroxymethyl)-3-m-tolyl-2-oxazolidinone, C11H13NO3,

Mj. 207.2, mp 76°C is prepared by the reaction of 3-methylaniline with glycidol followed
by condensation of the intermediate (an aminoalcohol) with diethyl carbonate [128].
CH n
Trade Name: Humoryl (Delalande, France).
626
3.4. Inhibitors of Serotonin Uptake
During the 1980s new drugs were developed that differed from tricyclics because
they were highly selective serotonin (5-HT) uptake inhibitors, (e.g., fluvoxamine,
paroxetine, fluoxetine, or sertraline). They proved to be effective antidepressants in
humans [129].
Fluoxetine enhances behavioral patterns induced in rodents by pharmacological
facilitation of 5-HT transmission [130]. It potentiates 5-HT-induced head twitches in
mice pretreated with pargyline, and has also been used as a tool in assessing 5-HT
transmission in several behavioral paradigms (self-stimulation test). Nevertheless, in
the behavioral despair test, where rats are immobile after a short period of swimming
in a restricted place, fluoxetine does not significantly reduce the duration of immobility
as is the case following administration of antidepressants that inhibit biogenic amine
uptake [106], [131]. Fluoxetine and related compounds are specific 5-HT uptake
inhibitors. They have no affinity for receptors such as cholinergic (muscarinic), a-
adrenergic, or histaminergic, and they possess lower, cardiovascular and sedative side
effects than the tricyclic antidepressants. Trazodone is an inhibitor of synaptosomal 5-
HT uptake but is also a 5-HT antagonist (see Section 3.6) [132].
The compounds described below are specific inhibitors of 5-HT uptake. An exception
is oxaflozane, which also inhibits NA uptake.
Citalopram [59729-33-8], l,3-dihydro-l-[3-(dimethylamino)propyl]-l-(4-fluorophe-

nyl)-5-iso-benzofurancarbonitrile, C20H21FN2O, 324.40, hp (0.004 kPa)
175-181 °C, hydrobromide mp 182-183 °C. Citalopram is prepared as follows [133]:
Citalopram is also used as a geriatric drug [134].
Trade Names: Cipramil (Lundbeck, U.K.), Seropam (Zeria).
627
Femoxetine [59859-58-4], (3/?-^ra/2^)-3-[4-(methoxy)phenoxymethyl]-l-methyl-4-
phenylpiperidine, C20H25NO2, 311.43. This compound is prepared as follows [1351:
This 5-HT uptake inhibitor is as effective as amitriptyline in the treatment of

depression, but displays fewer side effects.
Trade Name: Malexil (Ferrosan, Bristol-Myers, Knoll).
Fluoxetine [54910-89-3], A^methyl-3-[4-trifluoromethylphenoxy-3-phenylpropyl-

amine, CjyHigFsNO, 309.33, oxalate mp 179-182 °C (decomp.). Fluoxetine is pre
pared as follows [136]:
1)b,h,
2) soci,'' CH,
CH,
I
H
This 5-HT uptake inhibitor is reported to display fewer antimuscarinic side effects
than tricyclic antidepressants.
Trade Names: Adofen (Ferrer, Spain), Fluoxeren (Menerini, Italy), Fontex (Lilly), Reneuron (Juste,
Spain), Prozac (Lilly).
Fluvoxamine [54739-18-3], 5-methoxy-4'-(tri-fluoromethyl)valerophenone(£)-0-(2-

aminoethyl)-oxime, C15H21F3N2O2, 318.35, maleate mp 120-121.5 T. Fluvoxamine
628
pCH^
NH.
O
OCH
N-O
NH.
The compound has a good selectivity for 5-HT uptake over noradrenaline uptake.
Trade Names: Avoxin (Krka, Yugoslavia), Dumirox (Kalifarma, Spain), Faverin, Fevarin, Floxyfral,
Floxytral, Myroxim (Duphar).
Oxaflozane [26629-87-8] 4-isopropyl-2-[3-(tri-fluoromethyl)-phenyllmorpholine,

C14H18F3NO, Mr 273.29, bp (0.0006 kPa) 52 °C, hydrochloride mp 164 °C. Oxaflozane
H,C CH
Trade Name: Conflictan (LTM Sarbach, France).
Paroxetine [61869-08-7], (-)-tra«s-4-(4-fluorophenyl)-3-{[3,4-(methylenedioxy)phe-

noxy]-methyl}-piperidine, C19H20FNO3, Mr 329.37, hydrochloride mp 118 C. This
piperidine derivative is prepared by condensation of 4-(4-fluorophenyl)-3-(hydroxy-
methyOpiperidine with 3,4-methylenedioxyphenol in the presence of dicyclohexylcar-
bodiimide [139].
‘NH
9 ”
Trade Names: Aropax (Beecham Laboratories, USA), Seroxat (Ferrosan).
Sertraline [79617-96-2], (15,45)-4-(3,4-dichlorophenyl)-l,2,3,4-tetrahydro-AT-methyl-

1-naphthylamine, C17H17CI2N, Mr 306.23, hydrochloride, mp 243-245 C. For the
synthesis of sertraline, see [140].
629
Trade Name: Lustral (Invicta and Pfizer, UK).
3.5. Lithium
Despite the discovery in 1949 of the value of lithium salts, their use as a therapy for
mania only became current at the end of the 1950s in Europe, and only in the early
1970s in the United States. Lithium salts have proven to be active in mania and to
reduce the frequency of attacks of manic depressive illness [141], [142]. In experimental
psychopharmacology lithium salts only show weak activity. A sedative effect may be
seen at high doses, but is less evident than with antipsychotics. Lithium salts do not
antagonize stereotypies induced by amphetamine or apomorphine (tests for neuroleptic
activity) nor the effects of reserpine or tetrabenazine (tests for antidepressant activity).
In manic patients, lithium salts improve slow-wave sleep but depress REM sleep;
lithium induces slow-wave activity, sometimes with superimposed fast frequencies [79].
The mechanism of action of lithium salts is poorly understood. Lithium acts on
biological membranes and reduces excitability at therapeutic concentrations (1 m Eq/
L). Lithium has similar ionic properties to sodium but is not the ideal substrate for the
transmembrane sodium pump and thus cannot maintain membrane potentials. This
leads to a decrease in excitability, which could correspond to the reduction of the
psychic reactivity of the patient. Nevertheless biochemical studies have demonstrated
that lithium (1-10 mEq/L) inhibits release of NA and DA but not that of 5-HT [143].
Second messengers, such as inositol phosphates, are released by hydrolysis of
membrane phosphatidylinositides after activation of the neurotransmitter receptors;
lithium can increase this release. Depletion of phosphatidyinositides reduces neuron
reactivity to muscarinic, oc-adrenergic, or other stimuli where phosphatidylinositol is
the second messenger. This suggests that lithium could preferentially act on hyperactive
cells which induce the manic depressive illness [144] and the noradrenergic system
which abnormally increases brain electrical activity.
Finally, recent studies have shown that lithium can interact with other antidepres
sants and enhance their efficacy by acting on 5-HT neurotransmission. Studies in rats
and cats have shown that tryptophan concentration and uptake are increased after
short- or long-term lithium treatment. Short-term treatment with lithium has no effect
on basal 5-HT release in the hippocampus or frontal cortex. Studies with lithium salts
on 5-HT function indicate that they act at various levels, including reuptake, release,
synthesis, storage, or receptor interactions; many of these effects are time, region, or
species dependent.
630
Trade Names: (Carbonate) Teralithe (Rhone-Poulenc Rorer, France), (gluconate) Neurolithium
(Labcatal, France).
3.6. Miscellaneous Antidepressants

Amfebutamone [34911-55-2], 2-(tert-butylamino)-3'-chloropropiophenone,
CigHigClNO, Mr 293.74, bp (0.0006 kPa) 52 °C, hydrochloride mp 233-234 °C. Amfe
butamone can be prepared as follows [145]:
Amfebutamone is an inhibitor of dopamine uptake.
Trade Names: Wellbatrin, Wellbutrin (Burroughs Wellcome).
Medifoxamine [32359-34-5], AT,iV-dimethyl-2,2-diphenoxyethylamine, CieHigNOa,

Mr 257.33, fumarate mp 128.5 °C. Medifoxamine is prepared as follows [146]:
CH
I
OH 1) soa^ O N. CH,
0^0 2) (CH,),NH )—i
o o
CH,
LiAIH* O N. CH,
(CH^CH,),©
The mechanism of action of medifoxamine is analogous to that of amfebutamone.
Trade Names: Cledial (Anphar-Rolland, France), Gerdaxyl (Gerda, France; Promesa, Spain).
631
Trazodone [19794-93-5], 2-{3-[4-(3-chlorophenyl)-l-piperazinyl]propyl}-l,2,4-tri-

azolo[4,3-fl]pyridin-3(2//)-one, C19H22CIN5O, M, 371.88, mp 86-87T, hydrochloride
mp 223 °C. The bicyclic starting material is prepared by condensation of 2-chloro-
pyridine with semicarbazide [147]:
H
Cl
The triazolopyridine derivative trazodone is special because it is not active in classical

animal models, such as reserpine antagonism [148], but potentiates the behavioral
changes induced by the 5-HT precursor 5-hydroxytryptophan. Nevertheless its efficacy
as an antidepressant drug has been proved in clinical trials, with fewer side effects (e.g.,
cardiotoxicity) and a larger safety margin than the tricyclics. Drowsiness is, however,
common [106]. Trazodone is a selective inhibitor of central 5-HT uptake and decreases
peripheral 5-HT uptake. It also increases the turnover of brain dopamine.
Trade Names: Beneficat (Nemi, Argentina), Depyrel (Abie, Israel), Desyrel (Angelini, Italy, Bristol-
Meyers, Mead-Johnson), Molipaxin (Roussel), Pragmazone (UPSA, France), Taxagon (Rhodia, Argen
tina), Tombran (Boehringer, Ingelheim), Trazodil (Unipharm, Israel).
Viloxazine [46817-91-8], 2-[(2-ethoxyphenoxy)methyl]tetrahydro-l,4-oxazine,

Ci3ffi9N03, Mr 237.3, hydrochloride, mp 185-186 °C. For preparation, see [149].
H
This derivative is devoid of cholinergic-type side effects and is as potent as the

standard tricyclic antidepressants. Viloxazine is particularly useful for treating depres
sion in the elderly.
Trade Names: Catarol, Vivalan, Vivarint (ICI).
632
3.7. Antidepressants Under
Development
Adinazolam [37115-32-5] is a triazolobenzodiazepine under development (Upjohn) as
an antidepressant and anxiolytic (preregistration). It has a rapid onset of action with
minimal anticholinergic side effects [150]. Brofaromine [63638-91-5], (a benzofiiranyl-
piperidine derivative, (Ciba-Geigy), is a selective, competitive, reversible MAO-A in
hibitor (phase III clinical trials). Side effects were less frequent than with imipramine or
tranylcypromine [151]. Cericlamine [112922-55-1] (Jouveinal), a potent and selective
monocyclic 5-HT uptake inhibitor, is claimed to exhibit a better safety profile than other
new-generation antidepressants. Chemically related to buspirone, gepirone [83928-76-1]
is a partial 5-HT-lA agonist under development by Bristol-Myers Squibb [152].
Milnacipran [92623-85-3] is a cyclopropanecarboxamide derivative which behaves as
a 5-HT and NA uptake inhibitor (preregistration, Pierre Fabre). Wyeth-Ayerst (Amer
ican Home Products) has developed venlafaxine [99300-78-4], which has a binding
profile identical with that of milnacipran (phase III clinical trials). Mirtazapine [85650-
52-8] (Organon), an analog of mianserin, blocks presynaptic a-receptors (preregistra
tion). EEG studies on humans have confirmed its antidepressant potential [153]. The
nontricyclic triazolone derivative nefazodone [83366-66-9] is an antidepressant under
development by Bristol-Myers Squibb (preregistration). Farmitalia Carlo Erba (Erba-
mont) is developing rehoxetine [71620-89-8], which inhibits NA reuptake and blocks ot2-
receptors (phase III clinical trials). Ritanserin [87051-43-2], a thiazolopyrimidine is a
selective 5-HT2 antagonist. The compound is under development by Janssen (phase III
clinical trials) and is effective in mild to moderate depression, possibly associated with
anxiety. Inhibitors of brain type II phosphodiesterase, such as rolipram [61413-54-5]
(Schering AG), also have antidepressant activity. They possibly act by enhancing the
second messenger concentrations involved in P-adrenoreceptor activation [154]. Roli
pram was as effective as amitriptyline in treating patients with manic-depressive
psychosis [155].
Efforts are continuing to elucidate the mechanism of action of antidepressants, and
to develop new behavioral models with better predictability. Potentially interesting are
compounds with combined properties (e.g., MAO inhibitor with uptake blocking
activity).
633
4. Anxiolytics
Anxiety can be considered as a normal psychophysiological function which, in
certain situations, may present a pathological feature due to its intensity and the
excessive responses that it produces. Anxiety may be acute or chronic, and may take
many forms such as generalized anxiety, phobias, anguish, or panic attacks. The aim of
the anxiolytics is to treat the psychological and physiological effects of anxiety.
Alcohol and opium were probably the first substances used in the ancient times for
their anxiolytic and hypnosedative properties, despite their undesirable secondary
effects (habituation and dependence). It was not until the nineteenth century that
specific synthetic products became available for the control of sleep and anxiety,
notably bromine, with its frequent toxic effects (bromism), and chloral. At the begin
ning of the twentieth century, an important milestone was the discovery of the
hypnosedative barbiturates.
These derivatives of barbituric acid have since been extensively used for the treat
ment of insomnia Sedatives) and, at lower doses, for anxiety. Some members of
this family have potent sedative properties and are still employed as general anesthetics.
Minor modifications of the barbiturate structure gave the piperidinedione derivatives
which possess powerful sedative properties Sedatives). A further step was made in
the mid 1950s with the clinical use of meprobamate, a propanediol derivative, for the
specific treatment of anxiety. Up until this time, the treatment of sleep problems and
anxiety were often confused. Chlordiazepoxide, the first benzodiazepine (BZD), was
discovered in 1957 and led to a major advance in the treatment of anxiety disorders.
The BZDs, which possess powerful anxiolytic and sedative properties (see also ^ Se
datives) have superseded the barbiturates, thanks to their greater safety margins and
their lower toxicity [1561, [157]. Some benzodiazepines (e.g., chlordiazepoxide, clor-
azepate, or alprazolam) are almost exclusively prescribed as anxiolytics while others
(e.g., nitrazepam, fiunitrazepam, and triazolam) are exploited for their sedative hyp
notic effects. Midazolam is an exception, being used in anesthesiology to induce or
maintain narcosis, as premedication before anaesthesia, or during painful or disagree
able procedures which do not merit general anesthesia (endoscopy, biopsies). The
consumption of BZDs as anxiolytics or sedatives continued to grow until the end of
the 1970s when tolerance and dependence phenomena were reported after prolonged
administration. Consumption is now judged to be excessive.
The discovery of compounds with chemical structures different from those of the
BZDs, but with anxiolytic or hypnotic potential, was a further important step forward.
Anxiolytics normally possess both a sedative and hypnotic action, the latter may be
considered as an undesirable secondary effect, especially if diurnal somnolence results.
Recent progress offers clinicians anxiolytics without sedative activity. Examples are the
BZDs (bretazenil) or the cyclopyrrolones (RP 59037) [158]. Buspirone (an azaspirode-
canedione) is a case apart [159] and is already available as a nonsedative anxiolytic (see
p. 647).
634
A n x io ly tics
Animal tests for anxiety can be classified in three groups:
1) Tests based on conflict or conditioned fear: since the first experiments of Geller
and Seieter in 19601160], anxiolytics have been administered to animals to restore
certain behavioral responses previously suppressed by punishment
2) Tests based on anxiety generated by novel environments or situations: the social
interaction test and the elevated plus-maze test in which BZDs are active as
anxiolytic compounds
3) Tests in which anxiety is induced by chemical agents: BZDs antagonize the anxio-
genic effects of drugs such as fi- carbolines
4.1. Benzodiazepines
Since the early 1960s the study of BZDs has revealed five main pharmacological
properties that can be considered characteristic of these anxiolytic - hypnotic drugs:
anticonvulsant, myorelaxant, antiaggressive, anxiolytic, and sedative - hypnotic effects
1156]. The potency of these pharmacological effects depends on the pharmacokinetics
and on the receptor affinity of the tested compound.
Behavioral, biochemical, and electrophysiological studies indicate that these tran-
quilizing and sedative - hypnotic substances interact with neurotransmission mediated
by y-aminobutyric acid (GABA). BZDs increase the amplitude of the cat dorsal root
potential which is mediated by GABA. This increase in amplitude reflects the intensi
fied presynaptic inhibition in the spinal cord 1161], 1162]. Neurobiochemical research
in the domain of the sedative hypnotics has been stimulated by the discovery of specific
receptors in the CNS of rats and humans that recognize BZDs with tranquilizing or
sedative - hypnotic activity [163], [164]. The so-called BZD receptor consists of at least
three different subunits that form a pentameric macromolecular complex, the GABA
receptor complex, which constitutes a chloride-permeable ion channel [165]-[167].
Electrophysiological studies have shown that BZDs increase the frequency at which the
chloride channels open and consequently the flux of chloride ions at a given concen
tration of GABA [157].
635
4.1.1. 1,4-Benzodiazepines
Chlordiazepoxide [58-25-3], 7- chloro-2-methylamino-5-phenyl-3//-l,4-benzodiaze-
pine-4-oxide, C16H14CIN3O, 299.75, mp 236 -236.5 °C. This first pharmacologically
active member of the 1,4-benzodiazepine series is prepared as follows [168];
Chlordiazepoxide is used in the treatment of anxiety disorders, for the short-term

relief of anxiety symptoms, for symptoms of acute alcohol withdrawal, or preoperative
apprehension.
Trade Names: Librelease, Libritabs, Librium, Librizan, Tabrium (Roche), Retcol (Towa Yakuhin,
Japan), Serendyl (Nezel, Spain), Servium (Teve, Israel), Zeisin (ICN, USA).
Diazepam [439-14-5], 7- chloro-l,3-dihydro-l-methyl-5-phenyl-2/f-l,4-benzodiaze-

pin-2-one, C16H13CIN2O, 284.76, mp 125-126 °C. Diazepam is prepared as follows
[169]:
Desmethyidiazepam
Use of diazepam is analogous to that of chlordiazepoxide.
636
A n x io ly tics
Trade Names: Ansiolin (Scharper, Italy), Apozepam (A. L., Norway), Ceregulart (Kaken, Japan), Euro-
san (Mepha, Switzerland), Levium (Sodelco, The Netherlands), Paxel (Marion, USA), Stesolid (Dumex,
Denmark, CP Pharmaceuticals, UK), Valiquid, Valium, Valrelease (Roche).
Bromazepam [1812-30-2], 7-bromo-l,3-dihydro-5-(2-pyridinyl)-2//-l,4-benzodiaze-

pin-2-one, Ci4HioBrN30, 316.16, mp 237-238.5 °C (decomp.). This compound
can be synthesized from 2-(2-aminobenzoyl)pyridine in three steps [170]:
Indications are analogous to those of diazepam. Bromazepam, however, seems to be

more efficient in the treatment of neurotic anxiety disorders.
Trade Names: Bromazenil (Hexal, Germany), Compendium (Polifarma, Italy), Creosedin (Osiris,
Argentina), Durazanil (Durachemie, Germany), Lectopam, Lexomil, Lexotan, Lexotanil (Roche), Nor-
moc (Merckle, Germany).
Lorazepam [846-49-1], 7- chIoro-5-(2- chlorophenyl)-l,3-dihydro-3-hydroxy-2//-l,4-

benzodiazepin-2-one, C15H10CI2N2O2, Mr 321.16, mp 166-168 °C. Lorazepam is pre
pared as follows [171].
637
This short-acting compound is prescribed for management of anxiety disorders or
anxiety associated with depressive symptoms.
Trade Names: Almazine (Steinhard, UK), Ativan (Wyeth), Emotival (Armstrong, Argentina), Lorasolid
(Dumex, Denmark), Lorax (Wyeth), Pro Dorm (Schiirholz, Germany), Tavor (Wyeth), Temesta
(Ferrosan, Germany; Wyeth), Wypax (Yamanouchi, Japan).
Oxazepam [ 604-75-1 ], 7- chloro-l,3-dihydro-3-hydroxy-5-phenyl-2//-l,4-benzodi-

azepin-2-one, C15H11CIN2O2, 286.74, mp 205-206 °C. A synthetic pathway analo
gous to that of lorazepam leads to oxazepam 11721.
This short-acting compound is prescribed for the short-term relief of anxiety symp
toms. Anxiety associated with depression as well as management of anxiety, tension,
agitation, and irritability in the elderly are also responsive to oxazepam therapy. This
compound is sometimes used as an hypnotic.
Trade Names: Limbial (Chiesi, Italy), Noctazepam (Brenner, Germany), Praxiten, Serax, Serenid,
Seresta (Wyeth), Propax (Cipan, Portugal), Serepax (Wyeth, Ferrosan, Denmark), Sobril (Kabi Vitrum,
Sweden), Zaxopam (Quantum, USA).
Clorazepate [57109-90-7], 7- chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-l//-l,4-ben-

zodiazepine-3-carboxylic acid, dipotassium salt, C16H11CIK2N2O4, M, 408.93. This
compound (used as its dipotassium salt) is prepared as follows [173]:
638
A n x io ly tics
It is suitable for the symptomatic relief of acute alcohol withdrawal or, as adjunctive
therapy, in the management of partial seizures.
Trade Names: Belseren (Mead-Johnson), Mendon (Dainippon, Japan), Transene, Tranxilium (Clin-
Midy, France), Tranxene (Abbott, USA; Boehringer Ingelheim, Germany; Clin-Comar-Byla, France),
Tranxilene (Clin-Comar-Byla, France).
Prazepam [2955-38-6], 7- chloro-l-(cyclopropylmethyl)-l,3-dihydro-5-phenyl-2//-l,4-

benzodiazepin-2-one, C19H17CIN2O, Mr 324.83, mp 145-146 °C. Alkylation of des-
methyldiazepam using sodium hydride and cyclopropylmethyl bromide affords praze
pam [174].
\ o
Cl
Analogously to diazepam, prazepam is suitable for treating anxiety disorders or

short-term relief of anxiety symptoms.
Trade Names: Centrax (Parke Davis), Demetrin (Godecke, Germany, Substantia, Austria, Parke Davis),
Lysanxia (Substantia, France), Prazene (Parke Davis), Trepidan (Sigma Tau, Italy), Vestran (Warner-
Chilcott).
Camazepam [36104-80-0], 7- chloro-l,3-dihydro-3-(iV,iV-dimethylcarbamoyl)-l-

methyl-5-phenyl-2//-l,4-benzodiazepinone, C19H18CIN3O3, Mr 371.82, mp 173- 174 °C.
Camazepam is prepared as follows [172], [175]:
Trade Names: Albego (Boehringer Ingelheim; Farmasimes, Spain; Inpharzam, Switzerland), Limpidon,
Nebolan.
639
Etizolam [40054-69-1], l-methyl-6-(2- chlorophenyl)-8-ethyl-4//-5-triazolo[3,4-c]

thieno-[2,3-6’]-[l,4]diazepine, C17H15CIN4S, M, 342.85, mp 147-148 °C. Treatment of
the starting thienodiazepin-2-one with phosphorus pentasulfide in pyridine affords the
2-thione derivative which, by subsequent reaction with hydrazine, yields the 2-hydra-
zino compound. Final cyclization with azeotropic removal of water gives etizolam
11761.
Trade Names: Depas (Yoshitomi, Japan), Pasaden (Farmades, Italy).
Adinazolam [37115-32-5], 8- chloro-l-(dimethylamino)methyl-6-phenyl-4//-5-tria-

zolo-[4,3-fl][l,41benzodiazepine, CigHigClNs, M, 351.84, mp 165-166 “C. A synthesis
of adinazolam starting from nonbenzodiazepine intermediates has been developed. The
key step is the conversion of an aminoquinazoline into a benzophenone bearing a
potential triazole ring 1177].
Trade Name: Deracyn (Upjohn).
Alprazolam [28981-97-7], 8- chloro-l-methyl-6-phenyl-4//-5-triazolo[4,3-fllfl,4]benzo-

diazepine, C17H13CIN4, M, 308.77, mp 228-228.5 °C. Alprazolam can be prepared as
follows [178] :
640
A n x io ly tics
This anxiolytic is less sedative than diazepam, and is useful in the treatment of
anxiety associated with depression.
Trade Names: Constan (Takeda, Japan), Frontal, Solanax, Tafil, Trankimazin, Xanax, Xanor (Upjohn),
Valeans (Valeas, Italy).
Ketazolam [27223-35-4], 11- chloro-8,12Z?-dihydro-2,8-dimethyl-12Z;-phenyl-4//-[l,3]-

oxazinol3,2-t/] Il,4]benzodiazepine-4,7(6//)-dione, C20H17CIN2O3, Mr 368.82, mp
182 -183.5 °C. Ketazolam is prepared in a one-step synthesis 1179]:
This compound is used as an anxiolytic with a long-term effect.
Trade Names: Anseren (Ciba-Geigy, Switzerland), Ansieten (Exa, Argentina), Anxon, Loftram, Sedo-
time (Beecham), Marcen, Parcil (Antibioticos, Spain), Unakalm (Upjohn).
Clotiazepam 133671-46-4 ], 5-(2- chlorophenyl)-7-ethyl-l,3-dihydro-l-methyl-2//-

thienoI2,3-c]-l,4-diazepin-2-one, C16H15CIN2OS, Mr 318.82, mp 105-106 °C. 2-
Amino-3-(2-chlorobenzoyl)-5-ethylthiophene, prepared by reaction of butyraldehyde
with 2-chloro-1-cyanoacetophenone and sulfur in the presence of triethylamine as
catalyst, can be converted to the corresponding aminoacetamide derivative via two
methods (Fig. 3) 1180]:
This derivative is an anxiolytic thienodiazepine with apharmacological profile ana
logous to diazepam.
Trade Names: Clozan (Roerig, Belgium), Distensan (Esteve, Spain), Rize (Yoshitomi, Japan), Rizen
(Puropharma, Italy), Tienor (Farmaka, Italy), Trecalmo (Tropon, Germany), Veretran (Latema,
France).
641
ClCOCH,NHCOOCH,C.H, CH3CH3CH3CHO ^
"O s, (CH3CHj)3N
CH3CHj^^S"^NHCOCH3NHCOOCH,C,H, CH3CH3-^S"^NH,
CH31
NaH
Figure 3. Synthesis of clotiazepam
Bentazepam [29462-18-8], l,3,6,7,8,9-hexahydro-5-phenyl-2//-[l]benzothieno[2,3-^]-

l,4-diazepin-2-one, C17H16N2OS, Mj. 296.38, mp 251-253 °C, can be prepared as
follows 1181]:
Trade Name: Thiadipone (C.S.I.C., Spain).
Halazepam [23092-17-3], 7- chloro-l,3-dihydro-5-phenyl-l-(2,2,2-trifluoroethyl)-2//-

l,4-benzodiazepin-2-one, C17H12CIF3N2O, 352.75, mp 164-166 °C. Halazepam is
prepared as shown in Figure 4 1182].
This polyfluoroalkyl analogue of diazepam exhibits anxiolytic activity through its
metabolite iV-desmethyldiazepam. This benzodiazepine has a long-lasting effect and is
prescribed for treatment of anxiety disorders.
642
A n x io ly tics
Figure 4. Synthesis of halazepam
Trade Names: Alapryl (Menarini, Spain), Pacinone (Delagrange, Belgium), Paxipam (Schering Corp.,
UK).
4.1.2. Other Benzodiazepines

Tofisopam [22345-47-7], 7,8-dimethoxy-l-(3,4-dimethoxyphenyl)-5-ethyl-4-methyl-
S//-2,3-benzodiazepine, C22H26N2O4, M, 382.46, mp 156-157 °C. This 2,3-benzodi
azepine is prepared as follows 1183]:
Tofisopam exhibits anxiolytic activity without the classical side effects of 1,4-benzo
diazepines (hypnotic, anticonvulsant, myorelaxant effects) and does not affect the
psychological faculties.
643
Trade Names: Grandaxin (Egis, Hungary; Ozothine, France), Seriel (Fabre, France), Tavor (Gerardo
Ramon, Argentina).
Clobazam [22316-47-8], 7- chloro-l-methyl-5-phenyl-l//-l,5-benzodiazepine-2,4(3//,

5//)-dione, C16H13CIN2O2, Mj. 300.74, mp 180-182 °C. Clobazam is prepared as
follows 1184]:
HOOCCHjCOOCHjCHj
PClj
COOCH,CH,
Cl Zn, HCl
Trade Names: Clarmyl (Roussel-Iberica, Spain), Frisin, Frisium, Karidium, Noiafren,, Sentil (Hoechst),
Urbadan, Urbanol (Roussel), Urbanyl (Diamant, France, Roussel).
4.2. Carbamates
Meprobamate [57-53-4], 2-Methyl-2-propyl-l,3-propyldicarbamate, C9H18N2O4, M,
218.25, mp 104-106 °C. Meprobamate is prepared as follows [185]:
cocij, cicoo'''''xôcoci
H3C H3C
NH3 HjNCOO (•ÔCONHj

CHj
H3C
Meprobamate is an anxiolytic agent which has anticonvulsant, myorelaxant, and

sedative properties [160], but it does not directly interfere with the GABA-receptor
complex. The potentiation of the release of adenosine by meprobamate may account for
its central effects [186]. This carbamate derivative has been used for the management
of anxiety disorders and tension states but has been superseded by benzodiazepines.
644
A n x io ly tics
Trade Names: Amosene (Ferndale, USA), Artolon (Roter, The Netherlands), Cyrpon (Tropon, Ger
many), Equanil (Wyeth, Clin-Comar-Byla, France), Miltaun (Mack, Germany), Perequil (Merrell Dow
Lepetit), Aneural, Quaname, Quanil (Wyeth), Tranquilin (SAM-Parke-Davis, Belgium).
Phenprobamate [673-31-4], 3-phenylpropyl carbamate, C10H13NO2, Mr 179.21, mp

101-104 °C, for preparation see [187].
It has been given as an anxiolytic and myorelaxant.
Trade Names: Actiphan (Teikoku, Nagase, Japan), Ansepron (Fuso, Japan), Gamaquil (Siegfried,
Switzerland; Leo, Mekos, Pharmacia, Sweden), Kuilil (Embil, Turkey), Nelaxan (Toho, Japan), Para-
quick (Ohta, Japan), Phencol (Towa Yakuhin, Japan), Spantol (Nippon Chemiphar, Japan).
Tybamate [4268-36-4], Ar-butyl-2-methyl-2-propyl-l,3-propyldicarbamate,

C13H26N2O4, Mr 274.35, mp 49-51 °C, is prepared by reaction of 2-methyl-2-propyl-3-
hydroxypropyl carbamate with butyl isocyanate [188].
o o
<^CH3 i
H3C
Trade Name: Tybatran (Robins, USA).
Hydroxyphenamate [50-19-1], 2-hydroxy-2-phenylbutyl carbamate, C11H15NO3, Mr

209.24, mp 55-56.5 °C. This carbamate is prepared from j8-ethyl-j8-hydroxyphenethyl
alcohol and ethyl chloroformate followed by reaction with ammonia [189].
OCONH2
CH3
Trade Name: Listica (Armour).
645
4.3. Other Anxiolytics
Hydroxyzine [68-88-2], 2-{2-{4-[(4- chlorophenyl)phenylmethyl]-l-piperazinyl}ethoxy}-
ethanol, C21H27CIN2O2, Mr 374.92, mp 193 °C. Hydroxyzine is produced as follows
11901:
Cl
Cl
Hydroxyzine is an antihistaminic diarylalkylpiperazine which is used as an anxiolytic.

It has no cortical depressant activity, its anxiolytic action could be explained by its
suppressive effect on neuronal activity in subcortical areas. A myorelaxant activity has
also been demonstrated experimentally.
Trade Names: (Dihydrochloride) Alamon (Grelan, Japan), Atarax (Pfizer, Belgium; UCB-Fraysse,
France), Aterax (UCB, Belgium), Multipax (Rorer, USA), Orgatax (Organon), Ulgrax (UCB, Belgium),
Vistaril Parenteral (Pfizer), (Pamoate) Equipose (Pfizer).
[21715-46-8], 6- chloro-2-ethylamino-4-methyl-4-phenyl-4/f-3,l-benzoxa-
Etifoxine
zine, C17H17N2O, Mr 300.79, mp 90 °C, hydrochloride, mp 150 °C. Etifoxine is produced
as follows 1191]:
In rodents, etifoxine proved to be an anxiolytic. It possesses sedative, antiaggressive,

anticonvulsant, and anticonflict effects 1192]. Etifoxine enhances GABA-mediated
neurotransmission.
Trade Name: (Chloride) Stresam (Beaufour, France).
646
r
Alpidem [82626-01-5], 6- chloro-2-(4-chlorophenyl)-N,A/-dipropylimidazo[l,2-fl!]pyri-
A n x io ly tics
dine-3-acetamide, C21H23CI2N3O, 404.34, mp 140-141 °C. Alpidem is produced as
follows [193]:
Alpidem is an imidazopyridine derivative which produces anxiolytic-like effects in

some but not all models and anticonvulsant properties without myorelaxant and
sedative effects [194].
Whereas BZDs are largely nonselective for the subtypes of the GABA receptor
complex, alpidem displays a preferential affinity for the BZDi modulatory site
[195]. Moreover, relatively high doses of alpidem antagonize the myorelaxant and
sedative - hypnotic activities of diazepam.
Trade Name: Ananxyl (Synthelabo, France).
Buspirone [36505-84-7], 8-[4-[4-(2-pyrimidinyl)-l-piperazinyl]butyl]-8-azaspiro[4.5]-

decane-7,9-dione, C21H31N5O2, 385.51, hydrochloride, mp 202 °C, is prepared as
follows [196]:
647
I 1) ClCHjCH.CHjCN
ll) LiAlH^
o
N=\
p + HjN(CHj)4-N^ N-< }
/ M—/
o
I Pyridine, reflux
In tests for predicting clinical anxiolytic activity, buspirone, an azaspirodecanedione

derivative, attenuates conflict behavior in pigeons, rodents, and monkeys. Buspirone is
less sedative than the classical BZDs as shown in experimental and clinical trials. It is
ineffective as an anticonvulsant against convulsions induced by pentylenetetrazol,
bicuculline, picrotoxine, or supramaximal electroshock. Similarly, no motor incoordi
nation or myorelaxant activity occurs in buspirone-treated animals [195].
Buspirone does not bind to the GABA receptor complex and does not affect BZD
binding. Its most evident interaction occurs at the 5-HTia receptor. This action is
supported by binding studies, anatomical localization, neurochemistry, electrophysio
logy, and animal behavior [197].
Trade Names: Anisal (Vita, Spain), Ansiced (Abello, Spain), Bespar (Bristol), Buspar (Astra, Bristol-
Myers, Mead-Johnson), Buspisal (Lesvi, Spain), Buspon (Deva, Turkey), Censpar (Bristol-Myers), Noral
(Almirall, Spain).
4.4. Anxiolytics Under Development

New agents‘have been reported which interact with the central BZD receptor
complex, but do not have a simple benzodiazepine structure. They appear to be
selective in their anti-anxiety action. Examples include bretazenil, abecarnil, FG-7516,
CGS 20625, and dipavlon. Bretazenil [84379-13-5] (Ro 166028-Roche) exhibits anti
conflict and anticonvulsant properties.Only mild sedation appears at doses needed
to produce anticonvulsant or anxiolytic effects, and potentiation of ethanol-induced
sedation is less pronounced than with diazepam. Unlike full agonists, physical depen
dence could not be induced in monkeys after administration of bretazenil, even at a
very high dose. Bretazenil is a partial agonist at the GABA-A receptor complex. It is in
clinical trials (phase III) for generalized anxiety disorders, panic attacks, and schizo
phrenia [198]. Abecarnil [111841-85-1] [199] (ZK 112119, Schering) belongs to the fl-
carboline family and is in phase III clinical trials. It is active as an anxiolytic but less
648
G e ria tric D ru g s
sedative or myorelaxant than diazepam. Like bretazenil, abecarnil must be considered
as a partial agonist at the GABA-A receptor complex. FG-7516 [83910-44-5] (Novo-
Nordisk) is structurally related to abecarnil and is also in phase III clinical trials
[200].
CGS-20625 [111205-55-1] is undergoing phase I clinical trials as a potent, selective
inhibitor at the central benzodiazepine receptor. It does not appear to have the side
effects of diazepam. This analogue of CGS-9895 (suspended) belongs to the cyclohep-
ta[Z?]pyrazolo[3,W]pyridin-3(2//)-one family. Dipavlon [90808-12-1] (RU 32698, Rous-
sel-Uclaf) is an imidazo[l,2-fl]pyrimidine with anticonvulsant and anxiolytic properties
but with few effects in tests used to predict sedation or motor impairment in rodents.
Anxiolytic and anticonvulsant effects are antagonized by flumazenil, the BZD antago
nist. Dipavlon acts as a partial agonist at the GABA-A receptor complex and is in phase
II clinical trials.
Suriclone [53813-83-5] (Rhone-Poulenc Rorer) is a cyclopyrrolone derivative which
acts at the GABA-A receptor complex. It does not induce physical dependence in mice
even at a high dose after a chronic treatment. Binding studies show that suriclone
interacts with a different binding domain to anxiolytic BZD. Clinical studies have
shown that suriclone is an anxiolytic with a low incidence of drowsiness and a low
dependence potential compared with BZD.
The discovery of the anxiolytic properties of the 5-HTia partial agonist buspirone has
given rise to a second generation of serotoninergic agents (e.g., gepirone, ipsapirone,
tandospirone, umespirone, zalospirone, and metanopirone). All these agents are, how
ever, of low efficacy in patients having been treated with BZDs (lack of muscle relaxant
and sedative properties). Other serotoninergic agents such as ritanserin (5-HT2 antago
nist) or ondansetron (5-HT3 antagonist) are effective in the treatment of generalized
anxiety disorders [201].
Among newer molecular approaches to anxiety, selective antagonists such Cl 988 or
L 365,260, for the brain cholecystokinin receptors as well as the angiotensin II antago
nist DuP 753 have been reported to be potential anxiolytics [202], [203].
5. Geriatric Drugs
Geriatric drugs include substances with cognition-enhancing properties that are used
to treat the mental manifestations of aging. The continual increase in the expected
lifespan in developed countries enhances the prevalence of conditions ranging from
mild age-associated memory impairments (AAMI) to senile dementias (SD). Neurode-
generative processes and atherosclerosis have been identified as possible etiologic
causes for certain types of dementias such as senile dementias of the Alzheimer's type
(SDAT) and multi-infarct dementia.
The search for geriatric drugs is characterized by the absence of unequivocal clini
cally effective reference compounds. Moreover, inability to identify neurobiological
649
processes that are specifically involved in memory formation in the brain makes the
preclinical evaluation of these compounds difficult. Behavioral models of learning based
on cognitive interpretations of rodent locomotor performances often remain the only
available testing procedure [2041 •
Although no currently available drug can stop the evolution of cognitive disorders,
this chapter focuses on important drugs that alleviate or correct some of the symptoms
of the disease.
5.1. Nootropics
The term nootropic denotes substances that do not act through a given neurotrans
mitter system, that are neither psychostimulant nor sedative, and that improve learning
performance or compensate for learning deficits induced by amnesic manoeuvres in
behavioral models. Although a number of geriatric drugs fall within this rather wide
unrestrictive definition, the classical nootropics are chemically related to their proto
type piracetam (2-pyrrolidinone derivatives). Their mechanism of action is not known,
although they are believed to act in the telencephalon [2051 • The toxicity of nootropics
is generally low.
Piracetam [7491-74-9], 2-oxo-l-pyrrolidineacetamide, C6H10N2O2, M^. 142.16, mp

151 -152 °C is prepared by condensing 2-pyrrolidinone with ethyl chloroacetate in the
presence of a metal hydride and then converting the ester into an amide with ammonia
[206].
o
/'NH,
Piracetam protects the brain from hypoxic insults and facilitates transcallosal sy
naptic transmission in animals. In addition to senile dementia, it is proposed for the
treatment of dyslexia in children and of cerebrovascular stroke.
Trade Names: Agivilen (Efeka, Germany), Ciclofalina (Almirall, Spain), Durapitrop (Durachemie,
Switzerland), Noostan (UCB, Belgium), Nootrop (UCB, Belgium), Novocetam (Beiersdorf, Germany),
Piracebral (Hexal, Germany), Stimucortex (Kalifarma, Spain).
Aniracetam [72432-10-1], l-(4-methoxybenzoyl)-2-pyrrolidone, C12H13NO3, Mr

219.24, mp 121 -122 °C is prepared by condensing 2-pyrrolidone with 4-methoxyben-
zoyl chloride [207].
650
0CH3
This piracetam-related cognition enhancer reduces glutamate receptor desensitiza

tion [208].
Trade Names: Draganon (Roche, Switzerland), Sarpul (Toyama, Japan).
Oxiracetam [62613-82-5], 4-hydroxy-2-oxo-l-pyrrolidineacetamide, C6H10N2O3, Mr

158.16, mp 165-168 °C. Oxiracetam can be prepared as follows [209];
^r-COOCHjCHj COOCH3CH3
HN -t- < ------^
'^C00CH3CH3 COCl
^COOCH.CH,
r
CH,CH,OCO.^ .0 CHjCHjONa
,COOCH,CH,
r COOCH,CH,
COOCH,CH,
.N.
O
ir
COOCH,CH,
- P'O
Pn:
NaBH, N
Cr°
NH,
A second route starts with 4-amino-3-hydroxybutyric acid which is 0-silylated and

dehydrated to give 2-oxo-3-trimethylsilyloxypyrrolidine. Alkylation with ethyl bromo-
acetate, deprotection of the alcohol, and ammonolysis afford oxiracetam.
Oxiracetam is more hydrophilic than aniracetam and is claimed to have a wider
therapeutic spectrum.
Trade Names: Neupan (SmithKline Beecham, Portugal), Neuractiv (Ciba-Geigy, Switzerland), Neuro-
met (ISF, Italy).
5.2. Cholinergic Drugs

Cholinergic drugs are used in cognitive disorders on the assumption that they
compensate for the deficiency of central cholinergic processing that is thought to
underly dementia [210]. This cholinergic hypothesis is supported by results from
learning experiments which show that antagonists at muscarinic receptors (e.g., sco-
651
polamine) induce impairment in animals and humans. Destruction of the principal

cholinergic projection system in the rodent brain produces similar effects, and a loss of
cholinergic terminals has been observed in the brains of patients suffering from
Alzheimer's disease.
5.2.1. Choline Analogues

Choline analogues or choline-containing precursors are used in an attempt to
increase the rate of brain acetylcholine synthesis. These compounds are expected to
be more effective than simple dietary supplementation with choline or choline- contain
ing lecithin.
Deanol [108-01-0], 2-(dimethylamino)ethanol, C4H11NO, Mr 89.14, bp 135 °C, is

prepared from dimethylamine and ethylene oxide 1211]. It also exists as the salts of
acetylglutamic, 4-acetamidobenzoic, succinic, and tartaric acids.
H3C
Deanol is metabolized and incorporated into the brain choline pool, thereby in
creasing choline availability [2121 • This compound may also have an effect on brain
phospholipid metabolism.
Trade Names: Acumen (Menarini, Spain), Bimanol (Polfa, Poland), Cervoxan (S.M.B., Belgium),
Deaner (Riker), Diforene (Choay, France), Pabenol (Gentili, Italy), Tonibral (Bouchara, France), Varesal
(Arzneimittelwerk, Germany).
Meclofenoxate [51-68-3], dimethylaminoethyl 4-chlorophenoxyacetate, C12H16CI2NO3,

Mr 293.22, mp 135 -139 °C. Meclofenoxate is obtained by condensing 4-chlorophenoxy-
acetyl chloride with 2-(dimethylamino)ethanol [2131 •
o CH3
CiA^ HCl
Trade Names: Analux (Polfa, Poland), Brenal (Tanabe, Japan), Cerutil (Arzneimittelwerk, Germany),
Helfergin (Promonta, Germany), Marucotol (Maruko, Japan), Mecloxate (Sawai, Japan), Proseryl (Funai,
Japan), Ropoxyl (Nippon Chemiphar, Japan).
Citicoline [987-78-0], cytidine 5'-sodium diphosphate choline ester, Ci4H25N4NaOiiP2,

Mr 456.33, is a nucleotide coenzyme that plays an important role in the metabolism of
phospholipids. It is prepared by reacting choline phosphate and cytidine 5'-phosphate
with a condensation reagent such as A^,AJ'-dicyclohexylcarbodiimide 1214] or tosyl
chloride [2151
652
NH
(CH,)3N*
Trade Names: Alaton (Zambon, Italy), Colite (Nippon Chemiphar, Japan), Corenalin (Kaken, Japan),
Ensign (Yamanouchi, Japan), Eumetabol (Llano, Spain), Nicholin (Takeda, Japan; Byk Procienx,
Brazil), Nicolsint (Von Boch, Italy), Nicolin (Morishita, Japan), Startonyl (American Cyanamid, USA).
5.2.2. Cholinesterase Inhibitors

Cholinesterase inhibitors are used with the rationale that they can increase the
efficiency of the remaining cholinergic terminals by inhibiting acetylcholine depletion.
Physostigmine [57-47-6], (3<25-d5)-l,2,3,3fl,8,8a-hexahydro-l,3fl,8-trimethylpyr-

rolo[2,3-Z>]-indol-5-ol methyl carbamate, C15H21N3O2, Mj. 275.34, mp 105-106 T, is
extracted from calabar beans [216].
Physostigmine restores learning performance in animals with lesions of the nucleus
basalis magnocellularis [217].
CH
H
Trade Names: Anticholium (Kohler, Germany), Antilirium (Forest, USA), Fiostin (Tubi Lux Farma,
Italy).
Tacrine [321-64-2], 9-amino-l,2,3,4-tetrahydroacridine, C13H14N2, Mj. 198.27, mp

183 -184 °C, can be prepared by different methods, the shortest is condensation of 2-
aminobenzonitrile with cyclohexanone [218].
This product is a known curare antidote. It has a longer half-life than physostigmine
and has been used with some success by oral route in Alzheimer's patients [219].
Tacrine competitively inhibits acetylcholinesterase and also modifies the resting con
ductance and responses of neurons in the hippocampus.
Trade Name: Cognex (Warner Lambert).
653
5.2.3. Thyrolibenn Analogues
Thyroliberin, also known as thyrotropin releasing hormone (TRH), is a hypothalamic
regulatory hormone. It also acts on cholinergic neurons to enhance high affinity choline
uptake and stimulate acetylcholine synthesis and release. See also ^Peptides and
Protein Hormones. Thyroliberin is of possible interest for the treatment of neurode-
generative processes, such as Alzheimer's disease and amyotrophic lateral sclerosis.
Protirelin [24305-27-9], 5-oxo-L-prolyl-L-histidyl-L-prolinamide, C16H22N6O4,

362.39, the natural TRH tripeptide is prepared by conventional peptide synthesis [220].
Trade Name. Hirtonin (Hoechst).
Posatireiin [78664-73-0], L-pyro-2-aminoadipyl-L-leucyl-L-prolinamide, C17H28N4O4,

Mr 352.44, mp 214-216 °C, is prepared by sequential coupling, amino acids being
activated as their pentafluoro esters. Prolinamide is condensed with N- carboxybenzyl-
leucine. The dipeptide is then deprotected and coupled with L-pyro-2-aminoadipic acid
[2211.
Posatireiin is a pseudopeptide which improves sequelae of head injury and subar

achnoid hemorrhage.
Trade Name: Pyladox (Dînippon).
5.3. Metabolically Active Drugs

Metabolically active drugs are heterogeneous compounds with different proposed
mechanisms of action. They help to restore deficient brain energy metabolism. Some of
the most prescribed cognition enhancers are members of this class.
Idebenone [58186-27-9], 2,3-dimethoxy-6-(10-hydroxydecyl)-5-methyl-l,4-benzoqui-

none, C19H30O5, Mr 338.45, mp 46-50°C, is prepared in five steps. Friedel - Crafts
acylation of 3,4,5-trimethoxytoluene with 1,10-decanedioic acid semiester affords a
654
partially demethylated keto acid which is esterified and then reduced twice. The
phenolic ring is oxidized with Fremy's salt to give the quinone 1222].
o
CH,0 OH
CH3O
o
Idebenone is a benzoquinone that is derived from the widely distributed ubiqui
nones. It accelerates ATP formation by activating the electron-transfer system. It has
free-radical scavenger properties, stimulates mitochondrial respiration, and reduces
membrane lipid peroxidation.
Trade Names: Aban, Avan (Takeda, Japan).
Nicergoline [27848-84-6], 5-bromo-3-pyridinecarboxylate (8jS)-l,6-dimethyl-10-

methoxyergoline-8-methanol, C24H2sBrN303, 484.40, mp 136-138 °C, is prepared
by reducing a lumilysergic acid derivative with LiAlH4 and acylating the alcohol thus
obtained with 5-bromo-3-pyridinecarboxylic acid chloride [2231 •
Trade Names: Duracebrol (Durachemie, Germany), Ergobel (Hormosan, Germany), Memoq (Godeke,
Germany), Nicergolyn (Farnex, Italy), NicerHexal (Hexal, Germany), Sermion (Farmitalia Carlo Frba;
Specia), Varson (Almirall, Spain).
Ergoloid mesylates, also called dihydroergotoxine or co-dergocrine, is a mixture of

the hydrogenated ergot alkaloids dihydroergocornine [25447-65-8], dihydroergocristine
[17479-19-5], and dihydro-a-ergocryptine [25447-66-9], and dihydro-)9-ergocryptine
[77528-01-9].
Dihydroergotoxine is among the most widely prescribed geriatric drugs. It has
vasoactive properties and increases brain oxygen tension and electrical activity [2241.
Trade Names: Circanol (Riker), Deapril-ST (Mead Johnson), Hydergine (Sandoz), Niloric (Ascher),
Trigot (Squibb).
655
Dihydroergocornine R = CH(CH3)j
Dihydroergocristine R = CHjCgHj
Dihydro-a-ergocryptine R = CH3CH(CH3)j
Dihydro-p-ergocryptine R = CH(CH3)CH2CH3
Bifemelane [90293-01-9], 2-(4-methylaminobutoxy)diphenylmethane, CisHasNO, Mj.

269.39, mp 117-121 °C, is prepared by alkylation of 2-hydroxydiphenylmethane with
1,4-dibromobutane and subsequent condensation with methylamine [2251 •
I
H
Bifemelane has antianoxic and anti-ischemic properties. It also exerts an indirect

cholinomimetic effect by increasing acetylcholine release [2261 •
Trade Names: Alnert (Mitsubishi, Japan), Celeport (Esai, Japan).
Vinpocetine [42971-09-5], C22H26N2O2, 350.46, mp 147-153 °C is prepared by

esterification of vincaminic acid [227].
Vinpocetine is a Vinca alkaloid. It increases cerebral blood flow and glucose utilization,
and inhibits brain edema formation produced by cerebral metabolic inhibitors [224].
Trade Names: Cavinton, Ceractin (Ayerst), Eusenium (Thiemann, Germany).
Propentofylline [55242-55-2], 3,7-dihydro-3-methyl-l-(5-oxohexyl)-7-propyl-l//-pur-

ine-2,6-dione, C15H22N4O3, Mr 306.37, mp 69-70°C, is prepared by reacting 3-
methyl-7-propylxanthine with 6-bromo-2-hexanone in refluxing sodium hydroxide
[228].
656
o 9
This alkylxanthine is structurally related to the naturally occurring psychostimulant

caffeine (methylxanthine). Propentofylline inhibits cyclic nucleotide phosphodi
esterases, thereby increasing the levels of intracellular second messengers [229].
Trade Name: Hextol (Hoechst, Japan).
Pyritinol [1098-97-1 ], bis(4-hydroxymethyl-5-hydroxy-6-methyl-3-pyridylmethyl)di-

sulfide, C16H20N2O4S2, Mr 368.48, mp 218-220 T, is prepared by reacting a salt of
3,4-bis(bromomethyl)-5-hydroxy-6-methylpyridine with potassium xanthogenate and
then hydrolyzing the intermediate with alcoholic ammonia [230].
Pyritinol consists of two pyridoxine (vitamin Bg) molecules linked by a disulfide

bridge. It is devoid of vitamin Bg-like activity and improves glucose metabolism in
patients with organic brain disorders based on disturbed cerebral glucose metabolism
[231].
Trade Names: Bonifen (Merck, Spain), Dinerfene (Azevedos, Spain), Divalvon-D (Nippon Kagaku,
Japan), Enbol (Merck, Japan), Encefavol (Bracco, Italy), Neuroxin (Yamanouchi, Japan), Sawaxin
(Sawai, Japan).
5.4. Antidepressants
Several atypic antidepressants that lack the anticholinergic activity of classical
tricyclic antidepressants are successfully used in the treatment of cognitive disorders.
Their activity may also be due to the alleviation of depression which often contributes
to a decline in cognitive performance in the elderly patient.
Citalopram (see Section 3.4) inhibits 5-HT reuptake and significantly improves
cognitive performance in Alzheimer patients [134].
Exifone [52479-85-3], 2,3,3',4,4',5'-hexahydroxybenzophenone, C13H10O7,

278.22, mp 270 °C, is prepared by the Friedel - Crafts acyla-tion of pyrogallol with
3,4,5-trihydroxybenzoic acid [232].
657
OH O

HO OH
HO OH
OH
Exifone shows an atypical antidepressant profile of activity in a range of standard

psychopharmacological tests [2331 and is also claimed to protect against hypoxia. This
metabolic enhancer has no anticholinergic properties and thus lacks associated side
effects.
Trade Name: Adlone (Pharmascience, France).
Indeloxazine [65043-22-3], 2-l(inden-7-yloxy)methyl]morpholine hydrochloride,

C14H18CINO2, Mj. 267.76, mp 155-156 °C, is prepared as follows [234]:
Indeloxazine
The two isomers are separated by fractional crystallization [234].

This antidepressant agent inhibits 5-HT and noradrenaline reuptake but has only
weak effects on neurotransmitter receptors. It is effective in treating neuropsychological
symptoms, the major side effect being gastrointestinal disorders.
Trade Names: Elen, Noin (Essex Nippon, Yamanouchi, Japan).
5.5. Miscellaneous Geriatric Drugs

Phosphatidylserine is extracted from bovine cerebral cortex. It is believed to act on
neuronal membrane fluidity and acetylcholine release. It improves learning perfor
mance in aged rats [235].
Trade Name: Bros (Fidia).
Acetylcarnitine [5080-50-2], C9H18CINO4, M, 239.70, mp 187 °C, is an endogeneous

substance. It is prepared by acetylation of L-carnitine [236].
658
r
H,C^0^^C00H
° î^(CH3)3cr
Acetyl-L-carnitine stereospecifically facilitates neuronal electrophysiological re

sponses to acetylcholine and 5-HT 12371.
Trade Names: Branigan (Glaxo, Italy), Nicetile (Slgma-Tau, Italy).
Nimodipine [66085-59-4], isopropyl 2-methoxyethyl l,4-dihydro-2,6-dimethyl-4-(3-

nitrophenyl)-3,5-pyridinedicarboxylate, C21H26N2O7, Mr 418.45, mp 125 °C, is prepared
as follows 1238]:
Nimodipine is a calcium channel antagonist used for its vasodilatatory and hemo
dynamic effects on cerebral blood vessels [2391.
Trade Name: Nimotop (Bayer).
5.6. Geriatric Drugs Under Development

The search for cognition enhancers is a rapidly growing field and numerous sub
stances are being investigated. The following are in the phase III stage of development.
Sabeluzole [104592-54-3] (R 58735) is a benzothiazole derivative under investigation by
Janssen. It has antihypoxic and anticonvulsant properties [240]. Denhufylline [57076-71-
8] (BRL-30892, Smith K-line Beecham) is an alkylxanthene derivative which shares the
phosphodiesterase-inhibiting properties of this class of drugs [2241. It is under inves
tigation in multi-infarct dementia. Pramiracetam [68497-62-1] (CI-879) is a nootropic
closely related to piracetam under development by Parke-Davis for memory and
cognitive deficits following electroconvulsive shock therapy. Teniloxdzine [62473-79-4]
(Y-8894) is a nonpyrrolidine nootropic compound developed by Yoshitomi which has
also antiulcer properties in the gastrointestinal tract. Vdnacrine [118909-22-1] (HP-029,
Hoechst-Roussel) is an analogue of tacrine with cholinesterase-inhibiting properties. It
659
is under clinical investigation in Alzheimer's patients. Vinconate [70704-03-9] (OC-340,
Omnichem) increases brain oxygen levels and delays the onset of EEG abnormalities
during hypobaric hypoxia in humans.
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Antipsychotics/Neuroleptics

Marie-Christine DuBROEUca Rhone-Poulenc Rorer, Vitry-Siir-Scine, Trance

1. Introduction............................. 588 3.3. Monoamine Oxidase

3.1. Tricyclic Antidepressants... 610 5.3. Metabolically Active Drugs. . 654

3.1.3. Inhibitors of Dopamine Uptake 617 5.6. Geriatric Drugs Under

3.2. Tetracyclic Antidepressants . 620 6. References................................ 660

R = (CH2)CH(CH3)CH2N(CH3)2: alimemazine (X = H);

Promazine [58-40-2], 10-(3-dimethylaminopropyl)-10//-phenothiazine, C17H20N2S,

Chlorpromazine [50-53-3], 2- chloro-10-(3-dimethylaminopropyl)-10//-phenothia-

Triflupromazine [146-54-3], 10-(3-dimethylaminopropyl)-2-trifluoromethyl-10H-

Acepromazine [61-00-7], 2-acetyI-10-(3-dimethylaminpropyl)-10//-phenothiazine,

Alimemazine [84-96-8], 10-(3-dimethylamino-2-methylpropyl)-10H-phenothiazine,

Levomepromazine [60-99-1], 2-methoxy-10-(3-dimethylamino-2-methylpropyl)-

Cyamemazine [3546-03-0], 2- cyano-10-(3-dimethylamino-2-methylpropyl)-10/f-

Trade Name: Tercian (TheraplLx, France).

Thioridazine [50-52-2], 2-methylmercapto-10-[2-(l-methyl-2-piperidyl)ethyl]-10//-

Mesoridazine [5588-33-0], 2-methylmercapto-10-[2-(l-methyl-2-piperidyl)ethyl]-

Trade Names: Calodal (Heyden, Germany), Lidanil (Sandoz), Serentil (Sandoz).

Sulforidazine [14759-06-9], 2-methylsulfonyl-10-[2-(l-methyl-2-piperidyl)ethyl]-10//-

Trade Name: Inofal (Sandoz, Germany).

2.1.2.2. Piperidinopropyl-Substituted Phenothiazines

Pipamazine [84-04-8], 10-[3-(4- carbamoylpiperidino)propy]]-2-ch]oro-10//-phe-

Pericyazine [2622-26-6], 2- cyano-10-[3-(4-hydroxypiperidino)propyl]-10//-phe-

Piperacetazine [3819-00-9], 2-acetyl-10-[3-[4-(2-hydroxyethyl)piperidino]propyl]-

Trade Name: Quide (Merrell Dow).

Pipotiazine [39860-99-6], 10-{3-[4-(2-hydroxyethyl)piperidino]propyI}-AJ,Ar-dimethyl-

Spiclomazine [24527-27-3], 8-[3-(2- chloro-10//-phenothiazin-10-yl)propyl]-l-thia-

Trade Name: Diceplon (Yoshitomi, Japan).

Perazine [84-97-9], 10-[3-(4-methyl-l-piperazinyl)propyl]-10//-phenothiazine,

Trade Name: Taxilan (Promonta).

Prochlorperazine [58-38-8], 2- chloro-10-[3-(4-methyl-l-piperazinyl)propyl]-10//-

Trifluoperazi ne [117-89-5], 2-trifluoromethyI-lO- [ 3-(4-methyl-l-piperazinyI)propyI]-

Thioproperazine [316-81-4], 10-[3-(4-methyl-l-piperazinyl)propyl]-Ar,A(-dimethyl-

Trade Names: Majeptil (Specia, France), Mayeptil (Rhodia, Argentina).

Butaperazine [653-03-2], 2-butyryl-10-[3-(4-methyl-l-piperazinyl)propyl]-10//-phe-

Trade Names: Randolectil (Bayer, Argentina), Repoise (Robins, USA).

Perphenazine [58-39-9], 2-chloro-10-{3-[4-(2-hydroxyethyl)-l-piperazinyl]propyl}-

Trade Name: Frenolon (Egis, Hungary).

Thiopropazate [84-06-0], C23H28CIN3O2S, 446.00, bp (0.1 kPa) 214 — 218 C, is

Trade Names: Dartal, Dartalan (Searle).

Fluphenazine [69-23-8], 10-{3-[4-(2-hydroxyethyl)-l-piperazinyl]propyl}-2-trifluoro-

Acetophenazine [2751-68-0], 2-acetyl-10-{3-[4-(2-hydroxyethyl)-l-piperazinyl]pro-

Trade Name: Tindal (Schering, UK).

Carphenazine [2622-30-22], 10-[3-[4-(2-hydroxyethyl)-l-piperazinyl]propyl]-2-pro-

Trade Name: Proketazine (Wyeth, USA).

Two other compounds are analogous to the phenothiazines described above:

Homofenazine [ 3833-99-6 ], 10-{3-[hexahydro-4-(2-hydroxyethyl)-l,4-diazepine-l-yl]-

Trade Name: Pasaden (Homburg).

A n tip sy c h o tic s/N e u ro le p tic s

Trade Names: Dominal (Astra, Germany), Tolnate (SKF, UK).

Chlorprothixene [113-59-7], 2- chloro-9-(3-dimethylaminopropylidene)-9//-thioxan-

Thiothixene [3313-26-6], cA-9-[3-(4-methyl-piperazinyl)propylidene]-Ar,Ar-dimethyl-

Flupentixol [2709-56-0], 9-{3-[4-(2-hydroxyethyl)-l-piperazinyl]propylidene}-2-tri-

Clopenthixol [982-24-1], 2- chloro-9-{3-l4-(2-hydroxyethyl)-l-piperazinyllpropyli-

Trade Names: Ciatyl, Sordena, Sordinol (Kefalas).

Zuclopenthixol [53772-83-1], C22H25CIN2OS, M, 400.99, mp 84-85T, is the cis

Trade Names: Cisodinol, Clopixol (Lundbeck, Denmark); Sedanxol (Tropon, Germany).

Haloperidol [52-86-8], 4-[4-(4-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyro-

Bromperidol [10457-90-6], 4-[4-(4-bromophenyl)-4-hydroxypiperidinol-4'-fluorobu-

Trade Names: Azuren, Bromidol, Impromen (Janssen), Tesoprel (Organon, Germany).

Moperone [ 3871-82-7 ], 4 -fluoro-4-[4-hydroxy-4-(4-methy[pheny[)piperidino]butyro-

Trade Names: Luvatren, Luvatrena, Luvatrene (Cilag-Chemie).

Fluanisone [1480-19-9], 4'-fluoro-4-[4-(2-methoxypheny[)-l-piperazinyl]butyrophe-

Trade Name: Triperidol (Lagap, UK).